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\begin{document}

\title{Improving Targeted Small Molecule Drugs to Overcome Chemotherapy
Resistance}



\author[1]{amirhossein rismanbaf}%
\affil[1]{Islamic Azad University Tehran Medical Sciences}%


\vspace{-1em}



  
  \date{June 18, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Conventional cancer treatments face the challenge of therapeutic
resistance, which causes poor treatment outcomes. The use of combination
therapies can improve treatment results in patients and is one of the
solutions to overcome this challenge. Chemotherapy is one of the
conventional treatments that, due to the non-targeted and lack of
specificity in targeting cancer cells, can cause serious complications
in the short and long-term for patients by damaging healthy cells. Also,
the employment of a wide range of strategies for chemotherapy resistance
by cancer cells, metastasis, and cancer recurrence create serious
problems to achieve the desired results of chemotherapy. Accordingly,
targeted therapies can be used as a combination treatment with
chemotherapy to both cause less damage to healthy cells, which as a
result, they reduce the side effects of chemotherapy, and by targeting
the factors that cause therapeutic challenges, can improve the results
of chemotherapy in patients. Small molecules are one of the main
targeted therapies that can be used for diverse targets in cancer
treatment due to their penetration ability and characteristics. However,
small molecules in cancer treatment are facing obstacles that a better
understanding of cancer biology, as well as the mechanisms and factors
involved in chemotherapy resistance, can lead to the improvement of this
type of major targeted therapy. In this review article, at first, the
challenges that lead to not achieving the desired results in
chemotherapy and how cancer cells can be resistant to chemotherapy are
examined, and at the end, research areas are suggested that more
focusing on them, can lead to the improvement of the results of using
targeted small molecules as an adjunctive treatment for chemotherapy in
the conditions of chemotherapy resistance and metastasis of cancer
cells.%
\end{abstract}%



\sloppy


\textbf{Title:} Improving Targeted Small Molecule Drugs to Overcome
Chemotherapy Resistance

\textbf{Author:} Amirhossein Rismanbaf \textbf{(}
E-mail\textbf{:}amirhosseinrismanbaf@gmail.com)

\textbf{Affiliation:} Undergraduate of Cellular and Molecular Biology,
Department of Cellular and Molecular Biology, Faculty of Advanced
Science and Technology, Tehran Medical Sciences, Islamic Azad
University, Tehran, Iran

\textbf{Abstract:}

Conventional cancer treatments face the challenge of therapeutic
resistance, which causes poor treatment outcomes. The use of combination
therapies can improve treatment results in patients and is one of the
solutions to overcome this challenge. Chemotherapy is one of the
conventional treatments that, due to the non-targeted and lack of
specificity in targeting cancer cells, can cause serious complications
in the short and long-term for patients by damaging healthy cells. Also,
the employment of a wide range of strategies for chemotherapy resistance
by cancer cells, metastasis, and cancer recurrence create serious
problems to achieve the desired results of chemotherapy. Accordingly,
targeted therapies can be used as a combination treatment with
chemotherapy to both cause less damage to healthy cells, which as a
result, they reduce the side effects of chemotherapy, and by targeting
the factors that cause therapeutic challenges, can improve the results
of chemotherapy in patients. Small molecules are one of the main
targeted therapies that can be used for diverse targets in cancer
treatment due to their penetration ability and characteristics. However,
small molecules in cancer treatment are facing obstacles that a better
understanding of cancer biology, as well as the mechanisms and factors
involved in chemotherapy resistance, can lead to the improvement of this
type of major targeted therapy. In this review article, at first, the
challenges that lead to not achieving the desired results in
chemotherapy and how cancer cells can be resistant to chemotherapy are
examined, and at the end, research areas are suggested that more
focusing on them, can lead to the improvement of the results of using
targeted small molecules as an adjunctive treatment for chemotherapy in
the conditions of chemotherapy resistance and metastasis of cancer
cells.

\textbf{Keywords:}

Chemotherapy Resistance, Small Molecule, Tumor Microenvironment,
Immunomodulation, DNA Repair Mechanisms, Cancer Stem Cell

\textbf{Introduction:}

Cancer is a heterogeneous and highly complex disease that annually
claims the lives of millions of people, making it one of the leading
causes of death worldwide {[}1{]}. The number of deaths caused by cancer
is growing increasingly and predictions indicate that it will continue
to do so. Estimates show that in 2018, 9.6 million cancer-related deaths
occurred {[}2{]}. However, by 2030, it is projected that around 30
million people may die annually from cancer {[}2{]}. That is why cancer
is a very serious challenge for public health worldwide, and it becomes
increasingly widespread and severe every year. Although there are
innovative and diverse methods for cancer treatment, four treatment
methods are conventional and usually employed to combat cancer,
including surgery, radiation therapy, immunotherapy, and chemotherapy.
Chemotherapy, however, faces many challenges such as non-specific
targeting of cancer cells, treatment resistance, and cancer recurrence
even after successful treatment. The use of targeted small-molecule
drugs is one of the ways to improve the outcome of chemotherapy. Because
of their low molecular weight (\textless{}1000 Da) and small size, they
can bind to various targets outside and inside the cell {[}3{]}. Since
2001, when the first small molecule tyrosine kinase inhibitor (TKI)
drug, imatinib, by the US Food and Drug Administration (FDA), was
approved for clinical use, more than 80 small molecule drugs for cancer
treatment have been approved by the US FDA and the National Medical
Products Administration (NMPA) of China {[}4{]}. However, the
therapeutic results of targeted small molecules are limited. Cancer
cells use a variety of factors and strategies to fight and resist
chemotherapy. For this reason, to improve the results of treatments
based on small molecules as adjunctive therapy to overcome the
challenges of chemotherapy, knowledge and deep understanding of
chemotherapy resistance mechanisms and then determining the most
effective and main factors as targets for small molecules is very
crucial and important. In this study, most of these factors and
mechanisms are comprehensively examined in four titles including tumor
microenvironment, immunomodulation, DNA repair mechanisms, and cancer
stem cells. It is crucial and essential for drug designers and
scientists to extensively investigate these mechanisms for the proper
and effective design of targeted small molecule drugs as adjunctive
chemotherapy treatments.

\textbf{1. Tumor microenvironment (TME)}

The tumor microenvironment (TME) provides a secure environment for
cancer cells to evade the desired outcomes of various treatments.
Essentially, the TME is a complex and dynamic ecosystem composed of
diverse factors that play crucial roles in inhibiting apoptosis,
proliferation, migration, immune evasion, treatment resistance,
metastasis, metabolic reprogramming, and all stages of tumorigenesis
{[}5{]}. The tumor microenvironment factors are generally divided into
two main components: cellular components (such as tumor-associated
macrophages (TAMs), tumor-infiltrating lymphocytes (TILs),
myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts
(CAFs), and endothelial cells (ECs) which all of them are stromal
cells), and non-cellular components (such as growth factors, various
chemokines and cytokines, interstitial fluids, metabolites,
extracellular matrix (ECM) and exosomes) {[}5, 6{]}. Therefore,
targeting the TME is a potentially effective strategy for achieving
fruitful outcomes of cancer therapy, and small molecules can easily
penetrate the TME and ultimately reach tumor cells and affect them
{[}6{]}. The tumor microenvironment is a hypoxic and low-pH environment
{[}6{]}. The rapid growth of tumor cells causes hypoxia, which
subsequently causes the release of stimulating factors such as vascular
endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and
hypoxia-inducible factor-1\selectlanguage{greek}α \selectlanguage{english}(HIF- 1\selectlanguage{greek}α\selectlanguage{english}) {[}5{]}. Also, the condition of
hypoxia in TME affects the endothelial cells by secreting angiogenic
factors from the tumor and subsequently promoting angiogenesis {[}7,
8{]}. In the TME, the most abundant stromal cells are cancer-associated
fibroblasts (CAFs) that can produce abnormal extracellular matrix (ECM)
which supports tumor cell migration {[}9{]}. TME reshaping creates the
conditions for tumor cells to interact with surrounding fibroblasts,
immune cells, and endothelial cells, leading to the induction of a
variety of biological events, including angiogenesis, migration,
proliferation, immune system suppression, and drug resistance, which
ultimately causes tumor growth {[}9-18{]}.

One of the important events in the TME is cell interaction and cell
communication with the ECM because this interaction causes the release
of factors that play a role in ECM remodeling and immune evasion, which
ultimately strengthens treatment resistance {[}19{]}. Other important
events are the generation of exosomes by benign and malignant cells,
TME-specific metabolic patterns, and circulating deregulated microRNAs
that increase treatment resistance {[}19{]}. There are many different
types of immune cells in the TME that block the immune response, in
addition, around the tumor cells, there are a set of inflammatory
molecules that cause the failure to identify and eliminate cancer cells
by the immune system, which together make TME a complex and
heterogeneous space and they often cause an uncontrollable process in
the growth and development of tumors {[}5, 20-24{]}. On the whole, a
wide range of events and factors from biochemical agents, and a hypoxic
environment to abnormal mechanical forces cause treatment resistance
{[}19{]}. In the following, circumstances and various components of the
tumor microenvironment are discussed:

\textbf{1.1. Extracellular vesicles (EVs)}

Extracellular vesicles (EVs) act as intermediaries in intercellular
communication and are secreted by various types of cells {[}25{]}. These
vesicles are composed of a lipid bilayer that protects their contents
from enzymatic degradation {[}26{]}. They carry diverse biological
active molecules such as lipids, proteins, and various nucleic acids
including miRNA and lncRNA, and can regulate cellular processes and
functions, leading to changes in gene expression and activation of
multiple signaling pathways {[}25, 27-29{]}. Tumor-derived EVs can
modulate the tumor microenvironment {[}30{]}. EVs by transferring
surface markers and signaling molecules, nucleic acids, and oncogenic
proteins to stromal cells, can prepare the tumor microenvironment for
tumor growth, invasion, and metastasis {[}31-33{]}. Stromal and tumor
cells, by releasing EVs, cause heterogeneity and complexity in the tumor
microenvironment {[}25{]}. EVs create favorable conditions in the tumor
microenvironment for tumor growth and resistance to anti-cancer drugs by
transferring bioactive materials {[}25{]}. EVs contribute to drug
resistance through various mechanisms, including drug export and
sequestration, reduction of drug concentration in target sites,
transferring drug efflux pumps, mediating communication between cancer
and stromal cells, transfer of survival factors, apoptosis inhibitors,
and non-coding RNAs {[}25{]}. EVs not only play a role in metastasis and
drug resistance but also in immune suppression and angiogenesis, and
also, by providing growth factors such as TGF-\(\beta\)
(transforming growth factor-\(\beta\)) and various miRNAs, they
can convert mesenchymal stem cells and other bone marrow-derived cells
into tumor-supporting cells {[}25, 34, 35{]}.

One class of EVs is exosomes, which are involved in various cancer
events such as apoptosis escape, immune suppression/evasion, cell
proliferation, inflammatory responses, angiogenesis, invasion,
metastasis, and chemotherapeutic sensitivity {[}5, 36-39{]}. Not only
are exosomes involved in acquired drug resistance through various
cellular and molecular processes in the tumor microenvironment
(including DNA repair, epithelial-mesenchymal transition (EMT), immune
surveillance, and cell cycle), but also they contribute to drug
resistance through various pathways, including transporting drug efflux
pumps, direct drug export, and miRNA signaling {[}40-42{]}. By
transferring ABC transporters (drug efflux pumps) through exosomes, drug
resistance is promoted in sensitive cells {[}36{]}.

\textbf{1.1.1. Exosomal miRNAs}

miRNAs, or microRNAs, are a type of short ncRNAs that regulate various
important biological functions such as apoptosis, migration,
proliferation, differentiation, drug resistance, and invasion by
regulating gene expression {[}5, 43{]}. Cancer cells create an abnormal
expression of miRNAs through genetic or epigenetic changes, which
subsequently leads to abnormal expression of their target genes
{[}44-49{]}. miRNAs act as elements that promote the formation and
biological changes of TME {[}50-53{]}. Exosomal miRNAs derived from
tumors cause heterogeneity and phenotypic changes in TME and
subsequently promote uncontrolled tumor growth {[}20, 36, 54-58{]}.
Exosomal miRNAs derived from tumors by matrix reprogramming in TME
create a context for resistance to chemotherapy, tumor growth, immune
system escape, and metastasis {[}5{]}. Exosomal miRNAs secreted by
cancer stem cells that target immunosuppressive and anti-apoptotic
pathways can impart and develop drug resistance in susceptible
neighboring cells {[}36{]}. Exosomal miRNAs derived from cancer stem
cells (CSCs) cause inhibition of pro-apoptotic FOXO3a property and
activation of mTOR signaling pathway in sensitive cancer cells and they
can inhibit apoptosis and subsequently promote tumor progression,
therefore, drug-induced apoptosis is inhibited {[}36{]}. Horizontal
transfer of exosomal miRNAs derived from cancer cells can induce a
resistant phenotype of drug-resistant cells in sensitive cancer cells
and create resistance to a wide range of anticancer drugs, moreover,
miRNAs can be delivered from cancer cells to TME cells by exosomes and
modulate the process of drug resistance response in TME {[}59-61{]}.
Exosomal miRNAs derived from cancer stem cells and non-cancerous cells
help to drug resistance by creating different effects on target cells in
TME, in addition, exosomal miRNAs play a role in inducing resistance to
specific molecular target drugs and cytotoxic drugs {[}36{]}. Due to the
key role of miRNAs in cancer and their regulation of drug resistance in
a tumor-specific manner by some miRNAs, exosomal miRNAs can be
considered and used as potential cancer biomarkers for prediction and
diagnosis in a broad or specific tumor approach {[}36{]}. Exosomal
miRNAs derived from cancer cells and transferred to fibroblasts in the
tumor microenvironment (TME) promote differentiation of
cancer-associated fibroblasts (CAFs), subsequently, exosomal miRNAs
secreted by CAFs induce drug resistance in cancer cells through
induction of proliferation, metastasis, and inhibition of anti-tumor
effects of cytotoxic drugs such as cell cycle arrest and apoptosis
{[}36{]}. For example, the transfer of exosomal miR-21 derived from CAFs
to ovarian cancer cells led to inhibition of apoptosis and
downregulation in the expression of apoptotic peptidase activating
factor 1 (APAF1), as a result, resistance to treatment with paclitaxel
was increased {[}62{]}. Alterations in the Extracellular matrix promote
the widespread growth of cancer cells, angiogenesis, metabolic
reprogramming, and inflammatory response {[}5{]}. Primary tumor cells
release exosomal miRNAs such as miR-21, miR-155, miR-210, miR-1247-30,
and miR-124 that are transferred to normal fibroblasts (NFs), then, by
targeting proteins such as SPHK1, PTEN, and SOCS1, as well as activating
molecules such as FGF-2, FAP, TGF-\(\beta\), and bFGF induce
NFs conversion into CAFs, ultimately, ECM undergoes reshaping {[}5,
36{]}.

\textbf{1.1.1.1. Exosomal miRNAs and tumor-associated macrophages
(TAMs)}

The most abundant immune cell population in the TME is tumor-associated
macrophages (TAMs) {[}36{]}. TAMs are highly plastic cells that are
involved in various actions, including suppressing the immune system,
promoting tumor angiogenesis, and increasing resistance of tumor cells
to chemotherapy {[}63, 64{]}. Poor prognosis in many cancer types is
directly related to the number of TAMs in the tumor microenvironment
{[}65{]}. According to several studies, in several cancer types,
including lung, skin, colon, head and neck, bladder, and ovarian cancer,
exosomal miRNAs secreted by cancer cells can induce the transition of
macrophages to the TAMs {[}66-71{]}.

\textbf{1.1.1.2. Exosomal miRNAs and Epithelial-mesenchymal transition
(EMT):}

Epithelial-mesenchymal transition (EMT) is a process in which cancer
cells acquire increased motility and tremendous plasticity, caused by
loss of cell junctions and apical-basal polarity and acquisition of
mesenchymal characteristics {[}72, 73{]}. EMT cells are directly related
to metastasis, cancer progression, and drug resistance in various
cancers because they have an extremely invasive phenotype {[}74{]}.
There is ample evidence to demonstrate that the EMT process in the TME
can be modulated by exosomes released from cancer cells {[}41, 75,
76{]}. Xiao et al. showed that exosomal miRNAs involved in regulating
EMT, such as miR-191 and let-7a derived from melanoma, induced EMT in
primary melanocytes {[}77{]}. Additionally, studies have shown that
exosomal miRNAs are involved in activating or stabilizing EMT in primary
tumor cells {[}36{]}.

\textbf{1.1.1.3. Exosomal miRNAs and autophagy}

Autophagy is a catabolic process that removes damaged or redundant
macromolecules and organelles to maintain homeostasis and metabolic
adequacy {[}78{]}. This process is involved in escalating tumor
resistance against therapy and increasing tumor growth, as well as
upregulating autophagy frequently occurring leading to cell survival and
high energy supply during cancer initiation {[}36, 79, 80{]}. During a
phenomenon called cytoprotective autophagy a process caused by high
levels of autophagy and the creation of hypoxic TME, resulting in
oxidative stress, ultimately delays apoptosis and subsequently
contributes to treatment resistance {[}81, 82{]}. Upregulation of
exosomes and autophagy can act to induce an adaptive response under
cellular stress conditions in cancer cells {[}36{]}. Exosomes released
from cancer cells can induce the construction of reactive oxygen species
(ROS) and stimulate the secretion of tumor growth factors by
upregulation of autophagy in target cells {[}83{]}. Moreover, during a
drug treatment regimen, exosomes derived from cancer cells cause a
resistant phenotype in target cells by upregulation of cytoprotective
autophagy {[}84{]}. Exosomal miRNAs can control autophagy and play a
role as mediators in therapeutic resistance {[}36, 85, 86{]}. For
example, cisplatin-resistant non-small cell lung cancer (NSCLC) cells
secreted exosomal miR-425-3p, which targeted the AKT1/mTOR signaling
pathway and subsequently led to the upregulated autophagy activity and
reduced cisplatin treatment outcomes {[}87{]}.

\textbf{1.1.2. Exosomal lncRNAs (Long Non-coding RNAs)}

The transfer of exosomal lncRNAs between the tumor microenvironment and
tumor cells is involved in events such as reprogramming the tumor
microenvironment, growth, migration, and survival of cancer cells, as
well as the development of mechanisms that cause resistance to
chemotherapy {[}88{]}. In addition, because exosomal lncRNAs play a role
in malignancy and response to treatment, they could be employed as
biomarkers for many cancers {[}88{]}. There is evidence that lncRNAs
promote drug resistance in diverse cancers {[}88{]}. For instance,
lncRNA SBF2 (SET binding factor 2) induces temozolomide resistance in
glioblastoma cells during chemotherapy {[}89{]}. During tumor growth,
access to oxygen is limited due to poor vasculature within the
developing solid tumor mass, which is called hypoxia {[}88{]}. Under
hypoxia conditions, the hypoxia-inducible factor (HIF)-1\selectlanguage{greek}α \selectlanguage{english}pathway is
activated in tumor cells, which during oxygen stress, plays a role as an
adaptive mechanism {[}90{]}. Moreover, the hypoxia condition promotes
cell survival through the transcription of several lncRNAs {[}91, 92{]}.

\textbf{1.1.2.1. Exosomal lncRNAs and autophagy}

Because of the replenishment of energy supply and protection from
environmental stress, cancer cells upregulate autophagy, accordingly,
autophagy is a significant event in cancer {[}93{]}. Studies have shown
that because lncRNAs are key regulators of autophagy, they can protect
cancer cells against chemotherapy and environmental stress {[}88{]}. In
addition, autophagy induced by lncRNAs has a key role in the
proliferation and survival of tumor cells mediated by CAFs {[}94{]}.

\textbf{1.1.2.2. Exosomal lncRNAs and metabolic programming}

Metabolic activity in cancer cells is different from healthy cells
{[}88{]}. In hypoxia conditions, healthy cells begin to perform aerobic
glycolysis (Warburg effect), while cancer cells are highly dependent on
it {[}95{]}. The cancer cells which are proliferated continuously
require rapid production of ATP {[}88{]}. Furthermore, the rapid
production of ATP leads to the synthesis of many glycolytic
intermediates which go to subsidiary pathways and supply energy for
proliferating cancer cells {[}96{]}. In the metabolic reprogramming of
cancer cells, several signaling pathways play a role, including:

phosphatidylinositol 3-kinase (PI3K)/Akt, c-Jun N-terminal kinase (JNK),

extracellular signal-regulated kinase (ERK), and Ras {[}97{]}. Because
lncRNAs can regulate these signaling pathways, lncRNAs can affect the
metabolism of cancer cells {[}88{]}.

\textbf{1.2. Extracellular matrix (ECM):}

The ECM is a complex and diverse network of more than a hundred
proteins, including proteoglycans (heparan sulfate, chondroitin
sulfate), fibrous proteins (elastin, collagen), glycoproteins (laminins,
tenascin C (TNC), fibronectin 1 (FN1)), and glycosaminoglycans
(hyaluronic acid), which plays a role as a scaffold of organs and
tissues, as well as constitutes the largest component of the TME {[}6,
19, 98{]}. Although many tumor cells and diverse types of stromal cells
can produce ECM proteins, CAFs have a main and significant role in the
organization and composition of ECM {[}99, 100{]}. Moreover, the ECM
contains cytokines, chemokines, and growth factors released by stromal
and tumor cells {[}6{]}. The ECM regulates cell behavior and plays an
important role in tissue function and maintenance {[}101, 102{]}.
Accordingly, disruption of the mechanisms involved in the regulation of
ECM degradation, production, and remodeling causes pathological
conditions such as cancer and fibrosis {[}101, 103, 104{]}. Furthermore,
necessary signals for cellular differentiation, growth, and migration
are provided by ECM {[}102{]}. Each component of the extracellular
matrix, through cell surface receptors, induces signaling pathways to
cells and plays a role in tumor events including differentiation,
survival, migration, and metabolism {[}105, 106{]}. Moreover, ECM
heterogeneity provides evading growth suppressors, resisting cell death,
and sustaining growth signals for cells, as a result, has a key role in
tumor proliferation, also in tumor angiogenesis, metastasis, and
invasion {[}106, 107{]}. The ECM is responsible for cellular migration
out of the TME and cellular adhesion, although it functions as a
physical scaffold for cells {[}19{]}. The presence of stored diverse
soluble factors such as growth factors, cytokines, chemokines, and
angiogenic factors in the extracellular matrix creates a continuous
inflammatory condition that ultimately leads to the expansion of the
cellular repertoire {[}19, 108, 109{]}. In this inflammatory condition,
the deposition of a large amount of ECM protein occurs via facilitation
in the transformation of stromal fibroblasts into myofibroblasts, which
results in contraction and an increase in stiffness {[}109, 110{]}. One
of the determining and important factors in TME involved in cancer
treatment resistance is cell adhesion to ECM {[}111{]}. The interactions
of ECM components such as laminin, fibronectin, and collagen with
integrin provide a context for drug resistance mediated by cell adhesion
{[}111{]}. The efficacy of many drugs depends on the composition of the
cancer's ECM {[}102{]}. The dynamic adaptation of ECM is involved in the
invasion and progression of cancer and especially drug resistance, for
instance, ECM can adequately hinder drug delivery by increasing the
remodeling of microvascular endothelial cells {[}112{]}. Indeed, ECM
remodeling creates a physical obstacle that delays or prevents drug
delivery, thereby it increases drug resistance {[}113{]}. Furthermore,
ECM can activate survival proteins through survival pathways including
MAPK, p53, PI3K/AKT, and subsequently promote chemoresistance {[}102{]}.
Alterations in stiffness and elasticity of ECM impact drug delivery to
cancer cells, as well as pressure and diffusion, are factors related to
drug delivery in the interstitial spaces {[}102{]}. Drugs are delivered
to tumors through the pressure of blood circulation and the interstitial
areas {[}111{]}. In the interstitial areas, the ECM organization causes
an increase of fluid pressure through the physical obstacles of the
tumor mass and subsequently extremely prevents the desired results of
drug delivery {[}111{]}. In addition, an increase in the fluid flux from
the neoplasms to the surrounding environment due to the ample
proliferation of cancer cells prevents the adequate transfer of drugs
{[}114{]}. Indeed, the density of ECM cells plays a key role in the low
efficiency of drug delivery {[}115{]}.

Although all ECM components play a key role in tumor progression, the
role of collagen stands out {[}98{]}. Collagen can affect the behavior
of tumor cells through discoidin domain receptors, tyrosine kinase
receptors, integrins, and several signaling pathways {[}116{]}.
Furthermore, collagen can affect the activity of cancer cells by
interacting with ECM molecules including MMPs, lamins, fibronectin, and
hyaluronic acid {[}117{]}. Exosomes and miRNAs are other components that
have close interactions with collagen in cancer {[}118, 119{]}. In the
status that tumors are rich in collagen, the hypoxic condition is
common, leading to the promotion of cancer progression {[}116{]}.
However, heparan sulfate (CGKRK peptide), gelatin (anginex, small
geletic-1 binding peptide), laminin (IKVAV), fibronectin extra domain A
and B (anti-EDB aptide), and aggrecan (a conjugate of quaternary
ammonium) are some components of ECM that have therapeutic value
{[}98{]}.

\textbf{1.3. Cancer-associated fibroblasts (CAFs):}

Non-malignant stromal cells in the tumor microenvironment are crucial
for drug resistance and tumor progression {[}112{]}. Stromal cells are
polarized by their interaction with tumor cells, and through education
of tumor cells, they secrete diverse molecules, resulting in
pharmacokinetics regulation, immunosuppression, and metabolic
regulation, subsequently, they reduce therapeutic outcomes {[}112{]}.
The most common type of stromal cells are CAFs. CAFs by involvement in
ECM remodeling and metabolic reprogramming, as well as by secretion of
diverse factors such as cytokines (IL-6, IL-8, IL-10, etc.), growth
factors (hepatocyte growth factor, stromal cell-derived factor,
fibroblast growth factor, transforming growth factor), various
chemokines, metabolites, and exosomes (contain lncRNAs, miRNAs and
mitochondrial DNA (mtDNA)) which activate multiple signaling cascades,
cause drug resistance, and ultimately tumor recurrence {[}111, 112,
120{]}.

\textbf{1.4. Mesenchymal stem cells (MSCs):}

MSCs (or mesenchymal stromal cells) have the potential for self-renewal
and differentiation into various cell types {[}102, 106, 112{]}.
Moreover, MSCs can be involved in many cancer events such as
epithelial-mesenchymal transition, angiogenesis, anti-apoptosis,
metastasis, immunosuppression, pro-survival, and treatment resistance
especially drug resistance {[}112{]}. These cells can be inherently
resistant to chemotherapy and in various cancer types, they expand this
resistance among cancer cells {[}121-127{]}. MSCs can contribute to drug
resistance and quiescence of cancer cells by creating a pre-metastatic
niche for tumor cells {[}128{]}. Furthermore, they can move to
inflammatory areas, and subsequently, infiltrate the tumor {[}106{]}.
Indeed, MSCs migrate to the tumor site via the action of factors derived
from tumor cells, then, infiltrate the tumor and produce the necessary
factors for cancer cells {[}102{]}. Mesenchymal stem cells can cause
drug resistance through the following actions:

1. Direct cell-to-cell contact between MSCs and cancer cells that
triggers multiple signaling cascades in tumors {[}112, 129{]}.

2. Genetic mutations in MSCs: Genetic changes occur not only in tumor
cells but also in non-malignant cells, leading to latent tumor
recurrence in radiotherapy- and chemotherapy-treated patients {[}112,
130{]}.

3. Secretion of soluble factors: MSCs can release a variety of fatty
acids, cytokines, and growth factors that result in drug resistance
{[}102, 112, 131, 132{]}.

4. Differentiation of MSCs into CSC or CAF: Some characteristics of CSCs
are enhancing colony-forming capacity and pluripotency, obtaining drug
resistance along with loss of anchorage dependence, having the
capability to promote of metastasis and tumor progression, and
inherently resistant to chemotherapy, moreover, CAFs have a key role in
drug resistance and CAF-MSC cells (a type of CAF cells possessing
resembling function and phenotype of bone marrow-derived mesenchymal
stem cell (BM-MSC) in the tumor stroma) are involved in tumor growth,
the decline in cell apoptosis, increase in cell proliferation, and
resistance to chemotherapy; therefore, by differentiating MSCs into CSC
or CAF, they can cause treatment resistance {[}112{]}.

5. Release of exosomes: According to multiple studies, exosomes released
from MSCs promote chemotherapy resistance through mediation in
interactions between cancer cells and MSCs, specific mRNA molecules and
proteins transportation, and drug sequestration {[}112, 133{]}.

\textbf{1.5. Cancer-associated adipocytes (CAAs):}

Cancer-associated adipocytes (CAAs) are a type of stromal cells and an
important factor in TME that play a role in resistance to apoptosis,
angiogenesis, metastasis, drug resistance, and cancer cell invasion
{[}134-136{]}. CAAs promote cancer cell malignancy and tumor growth by
secreting pro-inflammatory cytokines, hormones, adipokines, adiponectin,
resistin, and leptin {[}109, 137, 138{]}. CAAs can also cause
chemoresistance by secreting exosomes, for instance, exosomal miR21s
derived from CAAs can inhibit apoptosis of cancer cells and promote
chemoresistance by binding to apoptotic protease-activating factor 1
(APAF1) in ovarian cancer {[}62, 109{]}.

In general, CAAs cause treatment resistance through the following
actions:

1. Secretion of various factors: Adipose tissue acts both as a site for
energy storage and as an endocrine organ, producing a wide range of
exosomes, adipokines, leptin, growth factors, and adipocytokines that
lead to treatment resistance {[}112, 139, 140{]}.

2. Extracellular matrix remodeling: CAAs are a crucial source for ECM
components, also, the property of ECM dynamic adaptation has an
important role in the invasion and progression of cancer, as well as
drug resistance {[}112{]}. CAAs release factors such as matrix
metalloproteinases (MMPs) and collagen VI protein, resulting in the
remodeling of ECM and chemotherapy resistance {[}141-144{]}. On the
whole, according to several studies, lipid metabolism and CAAs have an
intricate role in the regulation of cancer sensitivity to anticancer
drugs {[}112{]}.

3. Metabolism regulation: Since adipocytes perform energy storage, the
metabolic relationship between tumor cells and adipocytes can naturally
contribute to tumor progression {[}112{]}. Similar to CAFs, the
''Warburg effect'' and ''reverse Warburg effect'' could also cause drug
resistance mediated by adipocytes {[}139{]}. The amount of lactate
produced by adipocytes under hypoxia conditions increases significantly
{[}145{]}. Adipocytes also provide lipids for cancer cells to supply
their main energy, which can cause treatment resistance and tumor
progression, for instance, cancer cells take up exogenous free fatty
acids (FAAs) released by adipocytes and these endogenous lipid molecules
enhance the rate of fatty acid \selectlanguage{greek}β-\selectlanguage{english}oxidation (FAO), leading to extensive
synthesis of a\selectlanguage{english}ATP {[}112, 146{]}.

4. Alteration in the pharmacokinetics of chemotherapy: Pharmacokinetics
of chemotherapy is altered by CAAs commonly via two actions:

(a) Increase in drug clearance, (b) Alteration in drug distribution
{[}112{]}. Since the concentration of active drugs during treatment
plays a key role in the efficacy of cancer therapy, in adipocyte-rich
microenvironments such as adipose tissue, it is observed a local
decrease in cytotoxic chemotherapy activity due to decreased
concentration, which could contribute to chemoresistance {[}112, 147{]}.

\textbf{1.6. Acidosis:}

Acidification of the tumor microenvironment is related to metabolic
adaptation and reprogramming {[}148{]}. Moreover, tumor acidosis affects
metastasis, invasion, and therapeutic response and can act as a
regulator of tumor progression {[}148{]}. Tumor cells have high
metabolic demands that lead to the accumulation of a high amount
of\(\ \)n the TME, and due to the disordered nature of tumor
vasculature, effective removal of \(H^{+}\)from the
extracellular environment is prevented, accordingly, the accumulation of
\(H^{+}\) ions in the TME is intensified {[}148, 149{]}.
Consequently, it causes hypoxic conditions and changes in glycolytic
metabolism. In addition, in areas where oxidative conditions prevail,
the accumulation of \(H^{+}\) causes the hydration of carbon
dioxide, which meets the bioenergetic and biosynthetic needs of cancer
cells, these processes happen at a high speed {[}148{]}. Low pH in TME
can promote the motility of cancer cells and subsequently, influence
fibroblasts and activity and polarization of macrophages by bringing
about alterations in cytoskeletal dynamics {[}150{]}. In tumor regions
where the lowest pH conditions prevail, the highest rate of invasion can
occur and vice versa {[}148{]}. To adapt to the acidic environment,
tumor cells employ all enzyme systems {[}106{]}. In general, the
establishment of acidic conditions in the TME involves two events: CO2
by respiration and lactic acid formed by glycolytic metabolism
{[}106{]}. Evidence shows that acidic conditions overlap both in hypoxic
areas and at the tumor-stroma interface, which strongly influences tumor
invasion and proliferation {[}151{]}. Moreover, according to multiple
evidence, the conditions of extracellular acidosis create a suitable and
beneficial environment for dormant tumor cells to support the survival
of disseminated tumor cells and the formation of metastasis, and
subsequently, the chemotherapy-resistant phenotype is maintained {[}106,
152{]}.

\textbf{1.7. Metabolic reprogramming:}

Changes in energy metabolism are one of the specifications of tumor
cells since tumor cells proliferate abnormally and accordingly, are
dependent on the increased adaptation to the nutritional
microenvironment, which is operated by the metabolic reprogramming
{[}112, 153{]}. Due to the glucose deficiency in the tumor
microenvironment, the metabolism of cancer cells shifts to aerobic
glycolysis (the Warburg effect) {[}154{]}. The final product of this
metabolic process is lactate, which is associated with treatment
resistance {[}112, 155{]}. According to some evidence, other metabolic
features such as reversed Warburg effect, glutamine metabolism, and
metabolic symbiosis can cause acquired or adaptive drug resistance and
challenge anti-tumor treatment {[}156{]}.

Evidence suggests that disordered metabolism is involved in metastasis
and malignancy {[}111{]}. Severe reduction of amino acids such as
glutamine, tryptophan, and arginine and high levels of glycolysis are
observed in cancer cells {[}111{]}. The metabolic features of malignant
cells are regulated by tumor metabolic stress, leading to acidity,
nutrient deficiency, and oxygen competition in the TME {[}157{]}. Apart
from epigenetic and genetic alterations of cancer cells, the
interactions between various components of TME and metabolic competition
contribute to drug resistance and the growth and metastasis of tumor
cells {[}158, 159{]}.

\textbf{1.8. Interstitial fluid pressure (IFP):}

Abnormal lymphatic and blood vessels cause acidic pH, hypoxia, and high
interstitial fluid pressure (IFP) in TME and elevated IFP is a key
player in preventing adequate drug delivery to solid tumors {[}106{]}.
Factors such as abnormal ECM, high cell density, disruption of lymphatic
or venous drainage, and enhanced vascular permeability cause high IFP in
the tumor {[}160{]}. Abnormal proliferation of cancer cells leads to
mechanical compression of blood vessels and lymphatic vessels in the
confined area of the microenvironment, subsequently, meager lymphatic
drainage and poor blood flow are caused, leading to abnormal vascular
structures and a further reduction in a number of functional lymphatic
vessels {[}161{]}. As a result of excess fluid leakage from the vascular
system into interstitial space or interstitium (where accumulates and
swells the elastic ECM), IFP is increased, which is higher than in
normal tissue {[}106{]}.

The amount of drug entering the tumor and its absorption by cancer cells
affects the efficacy of chemotherapy {[}162{]}. For a drug to reach
cancer cells through blood vessels, it must be transferred from blood
vessels to interstitial fluid and then from interstitial space to
tissues {[}163{]}. Therefore, the amount of interstitial fluid pressure
is important for drug delivery, and high IFP conditions can reduce drug
transfer {[}162{]}. High IFP also compresses blood vessels, diverting
blood away from the tumor center to the periphery, as a result, drug
delivery is further reduced {[}162{]}.

\textbf{2. Immune cells:}

The immune system plays a crucial role in monitoring cancer and
responding to chemotherapy. Myeloid-derived suppressor cells (MDSCs),
tumor-associated macrophages (TAMs), dendritic cells (DCs), regulatory
and effector T cells, B cells, and natural killer cells (NKs) are the
main immune cells present in the TME {[}15, 164{]}. These cells can have
either opposing or stimulating effects on the tumor and play a key role
in tumorigenesis {[}15{]}. Immune cells also contribute to the
development of chemoresistance {[}165{]}. According to several studies,
the relationship between MDSCs and malignant cells has a significant
impact on chemotherapy resistance and immune system suppression {[}112,
166, 167{]}. At different stages of tumor development, diverse
populations of T cells are observed in the tumor microenvironment
{[}168, 169{]}. An increase in T-regulatory lymphocytes (T-reg)
infiltration in the tumor microenvironment is associated with
chemoresistance in several types of cancer, including colorectal, lung,
kidney, HNSCC, melanoma, ovarian, and glioblastoma cancer {[}170-176{]}.
Evidence suggests that tumor cells may manipulate local DCs to form
suppressive T cells, ultimately leading to drug resistance {[}177,
178{]}. Drug resistance and tumor progression can be caused by high
infiltration of tumor-associated neutrophils (TANs) in the TME
{[}179{]}. TANs can lead to acquired drug resistance in cancer due to
their capacity to increase angiogenesis, increase tumor cell
proliferation, and suppress the immune system {[}180, 181{]}. Moreover,
TANs can reduce the efficacy of many cancer drugs such as common
cytotoxic drugs and immune checkpoint inhibitors by activating various
signaling pathways {[}168{]}. Although NK cells may exhibit multi-drug
resistance-like activity, according to studies, this property can be
inhibited by drugs such as solutol HS-15 or verapamil {[}168,
182-184{]}.

TAMs are derived from circulating monocytes and are one of the most
abundant cells in solid tumors that have a significant impact on
suppressing the immune system in the TME, furthermore, TAMs play a role
in chemoresistance and tumor development {[}111{]}. Among the immune
cells present in the TME, macrophages have a prominent and critical role
in chemoresistance due to their capabilities and high numbers. TAMs are
the most abundant among immune cells in the TME, and their increased
infiltration into the microenvironment leads to unfavorable outcomes in
chemotherapy {[}112, 185, 186{]}. Generally, TAMs are divided into two
subgroups, M1 and M2, with the M2 phenotype playing a role in promoting
drug resistance and tumor progression {[}112, 187{]}. In cancer
conditions, macrophages are educated by the TME, and TAMs are usually
polarized from M1 to M2 {[}188{]}. Due to the interaction between TAMs
and tumor cells, under the pressure of treatment, TAMs are promoted by
tumor cells and differentiate into immunosuppressive M2-polarized
macrophages, leading to therapeutic resistance {[}112{]}. Moreover,
studies have demonstrated the type of M2 can lead to acquired drug
resistance in cancer cells {[}189-191{]}.

TAMs, like CAFs, release a wide range of soluble factors in the TME,
including chemokines, enzymes, interleukins, exosomes, etc, to combat
drug attacks, for instance, TAMs can prevent paclitaxel-induced tumor
cell death by expressing cathepsin S and B {[}112{]}. Moreover, through
overexpressed cytidine deaminase or CDA (an enzyme that is involved in
gemcitabine degradation), TAMs can promote chemotherapy resistance in
cancer {[}165, 192{]}. By secreting exosomal miR-365, TAMs can increase
the metabolism of gemcitabine in cancer cells, which ultimately leads to
apoptosis inhibition and tumor resistance promotion {[}193, 194{]}. TAMs
upregulate Gfi-1 in tumor cells by TGF-\selectlanguage{greek}β \selectlanguage{english}secretion, which ultimately
leads to reduced sensitivity of tumor cells to gemcitabine by inhibiting
HMGB1 (high mobility group box 1) and CTGF (connective tissue growth
factor) expression {[}195{]}. By expressing IGF, TAMs can cause
resistance to chemotherapy with albumin-binding paclitaxel and
gemcitabine {[}165, 196{]}. Additionally, TAMs can cause chemotherapy
resistance in pancreatic cancer by inducing EMT {[}197{]}. According to
evidence from prostate cancer treatment with ADT, CSCs can remodel
macrophages into TAMs, subsequently, through the IL6/STAT3 signaling
pathway, TAMs can increase stem-like features of CSCs and drug
resistance {[}112, 198{]}.

Overall, TAMs use various mechanisms to induce drug resistance,
including regulating CSC properties, transforming into M2 suppressive
phenotype, promoting EMT, releasing various cytokines, and suppressing
immune cells {[}112{]}.

\textbf{3.} \textbf{DNA repair mechanisms:}

Preserving the genome and transmitting a healthy genome to the next
generation is an essential task for living organisms {[}199{]}. However,
DNA is constantly exposed to both endogenous insults (such as
intracellular free radical oxygen species (ROS), etc.) and exogenous
genotoxic insults (such as ionizing radiation (IR), ultraviolet (UV)
radiation, chemotherapeutic drugs, etc.), that can damage to DNA
{[}199{]}. Although DNA damage is a crucial target for radiotherapy and
chemotherapy, it can also lead to the development of cancer {[}199{]}.
Therefore, to maintain genome integrity, living organisms rely on a
complex system and multiple mechanisms to counteract DNA-damaging
factors, collectively known as the DNA Damage Response (DDR) {[}200{]}.

Several DNA repair pathways are utilized to counteract DNA damage,
including:

(1) Base excision repair (BER), (2) Nucleotide excision repair (NER),

(3) Homologous recombination (HR), (4) Non-homologous end joining
(NHEJ),

(5) Mismatch repair (MMR), (6) Microhomology-mediated end joining
(MMEJ),

(7) DNA damage tolerance (DDT) (Translesion synthesis (TLS), template
switching (TS)),

(8) \(O^{6}\)-methylguanine-DNA methyltransferase (MGMT)
pathway,

(9) Fanconi anemia (FA) pathway, (10) Single-strand annealing (SSA)
{[}200-203{]}

Among these pathways, BER, MMR, NER, HR, and NHEJ are the major and
essential pathways in DNA repair {[}200, 201{]}.

Moreover, there are several types of DNA damage, including:

(1) Clustered damaged sites, (2) Base damage, (3) Single-strand breaks
(SSBs),

(4) Double-strand breaks (DSBs), (5) Sugar damage, (6) DNA
cross-linking~{[}204{]}

DSBs are the most destructive and the most deleterious type of DNA
damage for cells which can bring about cell death or carcinogenesis
{[}204{]}. Among the types of DNA damage, SSBs and DSBs are prominent
which can bring about genome rearrangement. The direct and indirect BER,
MMR, and NER pathways repair SSBs damage, while the SSA, NHEJ, and HR
pathways repair DSB damages {[}200, 205, 206{]}. Moreover, DNA adducts
and replication errors are repaired by the NER and MMR pathways,
respectively {[}200{]}.

To control the DDR, cells utilize epigenetics and miRNAs as regulators.
Epigenetic alterations in gene expression and tumor heterogeneity play a
key role, as a result, epigenetic chromatin regulation can influence the
mechanisms and pathways involved in the DNA repair process {[}207{]}.
Histone deacetylases (HDACs) can contribute to the preparation of
chromatin for DSB repair promotion via NHEJ and HR {[}207{]}.
Furthermore, DNA methylation is a common epigenetic mechanism in cancer
cells and gene inactivation {[}207{]}. Alterations in gene promoter
methylation status of DDR components are observed in diverse cancer
types including oral squamous cell carcinoma, thyroid cancer, non-small
cell lung cancer (NSCLC), neck squamous cell carcinoma, gastric cancer,
acute myeloid leukemia (AML), breast cancer, ovarian cancer, bladder
cancer {[}207-218{]}. Moreover, the methylation status of some DDR genes
can be employed as treatment response, prognostic, and diagnostic
biomarkers in diverse types of cancer {[}207{]}. miRNAs function as
regulators in various processes, including tumorigenesis, and
post-transcriptional control of DNA repair components, in addition,
miRNAs can regulate the expression levels of DNA repair genes and
subsequently modulate the sensitivity of cancer cells to DNA-damaging
agents {[}207{]}.

Chemotherapeutic agents commonly used include Topoisomerase I
inhibitors, Alkylating agents (such as cisplatin), and DNA Topoisomerase
II inhibitors {[}219{]}. During chemotherapy using Camptothecin (a
Topoisomerase I inhibitor), if SSB damage occurs, the BER pathway is
activated, and subsequently, PARP1 and APE1 enzymes are activated,
however, if DSB damage occurs, the HR and NHEJ pathways are activated,
followed by the HR pathway activating AMT and CHK1 enzymes, and NHEJ
activating DNA-PK enzyme {[}202{]}. When Etoposide (a Topoisomerase II
inhibitor) is prescribed, DSB damage occurs, which activates the HR and
NHEJ pathways {[}202{]}. The HR pathway activates ATM and CHK1 proteins,
and NHEJ activates DNA-PK {[}202{]}. When Cisplatin (an Alkylating
agent) is prescribed, DNA interstrand cross-link (ICL) damage
(activating HR and NER pathways) and intrastrand cross-link damage
(activating NER pathway) occur {[}202{]}. Then, the HR pathway activates
ATM and CHK1 proteins, and the NER pathway activates XPA, XPB, and XPG
proteins {[}202{]}.

\textbf{4. Cancer Stem Cells (CSCs)}

One of the reasons for cancer progression and treatment failure is
cancer heterogeneity {[}220{]}. Different cancer cell types in the tumor
contribute to tumor heterogeneity, and among these cells, cancer stem
cells (CSCs) are highly involved in the initiation and progression of
cancer as well as have self-renewal and differentiation abilities
{[}221{]}. Stem cells in cancers can be divided into two categories
based on their function:

(1) Resident cancer stem cells that can initiate the tumor,

(2) Migratory stem cells that metastasize and form tumors in another
location {[}221{]}.

Due to these capabilities, CSCs play a key role in tumor initiation,
drug resistance, metastasis, and cancer recurrence {[}222{]}. During
successful chemotherapy, although a significant portion of tumor cells
undergo apoptosis, a subset of CSCs may survive and cause cancer
recurrence {[}223, 224{]}.

There is a wide range of mechanisms and factors that contribute to CSCs
to promote chemoresistance, including:

(1) Tumor microenvironment (Autophagy, Inflammation, Adipocyte-released
factors, CAFs, Mesenchymal stem cells (MSCs), Extracellular matrix
(ECM), Hypoxia, Endothelial cells (ECs), Immune cells), (2) EMT
induction or activation of EMT-transcription factors,

(3) Self-renewal ability (high telomerase activity),

(4) High expression of CSCs markers (such as CD133, ALDH1, CD44, CD24+),

(5) Quiescence / Dormancy / low proliferation rate,

(6) Stemness genes (such as Bmi1 and Musashi (MSI)),

(7) Epigenetic mechanisms (DNA methylation, Histone modifications),

(8) Signaling pathways (such as Hedgehog pathways, Notch pathways, and
Wnt pathways),

(9) Resistant to DNA damage-induced cell death (Promoting the DNA repair
capability, Enhancing ROS scavenging, Activating the anti-apoptotic
signaling pathways), (10) Metabolism alteration,

(11) Higher expression of multi-drug resistance (MDR) or detoxification
proteins (Aldehyde dehydrogenase (ALDH), Drug-transporter proteins
(ABCG1, ABCB1)),

(12) Non-coding RNAs (ncRNAs) {[}220, 225-230{]}.

There is extensive evidence indicating that ncRNAs, including lncRNAs
and miRNAs, play a key role in regulating CSC capabilities such as
asymmetric cell division, cancer recurrence, tumor initiation,
self-renewal, and drug resistance {[}220, 231-236{]}. Moreover,
according to multiple studies, ncRNAs control the cancer progression and
growth and division of cancer stem cells by regulating downstream
signaling pathways and transcription factors {[}226, 237-240{]}.

\textbf{Discussion and Conclusion:}

Cancer cells employ a wide range of factors and mechanisms to resist
chemotherapy. Among these factors, the triad of CSCs, exosomes, and
ncRNAs are particularly prominent. CSCs not only utilize diverse
intracellular and extracellular mechanisms to develop chemoresistance
but also have a significant role in chemoresistance through their
interactions with various components of TME and other cancer cells.
Furthermore, It has also been established that CSCs play a crucial role
in recurrence after successful chemotherapy. As previously mentioned,
exosomes present in the microenvironment have a prominent role in
cellular communications and interactions between different components of
TME and cancer cells. Additionally, ncRNAs have an important role in
intracellular signaling pathways and intercellular communications
between CSCs and other factors. Therefore, it can be deduced that ncRNAs
are likely to have a significant impact on the function of mentioned
factors involved in chemotherapy resistance caused by CSCs. Moreover,
CSCs can utilize their high capacity of survival and chemoresistance to
stay alive after chemotherapy, as well as employ the combination of
exosomes and ncRNAs to spread chemoresistance among other cancerous
cells by establishing wide intercellular communications with tumor cells
and the tumor microenvironment components, ultimately leading to the
exacerbation of chemotherapy resistance and cancer relapse. Indeed,
ncRNA can be considered the most prominent factor among other factors in
the chemoresistance of CSCs. Therefore, an in-depth understanding of the
interactions between CSCs, exosomes, and ncRNAs is very important and
vital in achieving the desired chemotherapy results, and research in
these three fields is very necessary to understand their precise
function in chemotherapy resistance.

In addition, it is recommended that the use of smart nanoparticles as a
drug delivery method for small molecules could be an effective approach
for delivering a greater and more fruitful amount of small molecules to
cancer cells, considering the distinct conditions within the tumor
microenvironment (hypoxia, acidity, etc.). One of the challenges in drug
delivery is the limited understanding of drug targets. Large-scale
screening studies using CRISPR-Cas technology can help to improve our
understanding of high-priority drug targets.

On the whole, the application of the following strategies can improve
the design and therapeutic outcomes of small molecule drugs as
combination therapy for chemotherapy:

1. Focusing more research on interactions between CSCs, exosomes, and
ncRNAs as well as their function in chemotherapy resistance for a better
and deeper understanding of these areas.

2. Identifying the factors that maintain proper function and favorable
interactions between CSCs, exosomes, and ncRNAs to be considered as
targets for small molecule drugs so that targeting them causes effective
disruption in the function and interactions of these three components.

3. Launching extensive screening studies using CRISPR-Cas technology to
identify potential drug targets for the design of effective small
molecule drugs.

4. More research on drug delivery systems based on smart nanoparticles
to improve and increase their efficiency in the appropriate and
sufficient delivery of small molecule drugs to the tumor
microenvironment and cancer cells.

\textbf{Conflict of Interest:}

No conflict of interest has been expressed by the author.

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