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-β 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].
3. 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-linkingĀ [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].