The complex interplay of tumor-infiltrating cells in driving therapeutic resistance pathways

Abstract

Drug resistance remains a significant challenge in cancer treatment. Recently, the interactions among various cell types within the tumor microenvironment (TME) have deepened our understanding of the mechanisms behind treatment resistance. Therefore, this review aims to synthesize current research focusing on infiltrating cells and drug resistance suggesting that targeting the TME could be a viable strategy to combat this issue. Numerous factors, including inflammation, metabolism, senescence, hypoxia, and angiogenesis, contribute to drug resistance could be a viable strategy to combat this issue. Overexpression of STAT3 is commonly associated with drug-resistant cancer cells or stromal cells. Current research often generalizes the impact of stromal cells on resistance, lacking specificity and statistical robustness. Thus, future research should take notice of this issue and aim to provide high-quality evidence. Despite the existing limitations, targeting the TME to overcome therapy resistance hold promising and valuable potential.

Introduction

Drug resistance is a persistent and complex problem that diminishes the effectiveness of treatments and jeopardizes patient outcomes in cancer management [1]. Despite numerous studies dedicated to addressing drug resistance, the outcomes of these efforts have not yet reached a satisfactory level [2, 3]. In recent years, advancements in single-cell analysis, proteomics, genomics, and transcriptomics have facilitated a more detailed exploration of the specific mechanisms of drug resistance for many medicines [4, 5]. Simultaneously, there has been a growing focus on studying the tumor microenvironment (TME), which includes both infiltrating cells and noncellular components [6]. In addition to tumor cells, immune and stromal cells significantly influence the development of tumor [7]. Of these, infiltrated immune cells usually comprise T cells, B cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs), among others. Non-immune cells, including tumor-associated fibroblasts (TAFs), mesenchymal stem cells (MSCs), and bone marrow stromal cells (BMSCs), also constitute a significant portion of the stromal cells in the TME [8, 9]. Researchers have gained critical insights by recognizing that tumor development is contingent on the entire TME, not solely on tumor cells [10]. This realization has led to the identification of numerous therapeutic targets and the subsequent development of novel drugs [11]. Moreover, the interactions between different cell types in the TME provide researchers with a more profound insight into the mechanisms of treatment resistance. For instance, TAMs could induce chemoresistance in cancer through regulating glucose metabolism [12]. In prostate cancer, inhibiting PI3K has been shown to enhance the anti-tumor function of CD8 + T cells, thereby transforming “cold” tumors into immunotherapy-responsive cancers [13]. Therefore, we aim to synthesize current research focusing on infiltrating cells and drug resistance. By highlighting both the exciting findings and gaps, we envision to pave the way for overcoming drug resistance through strategies targeting tumor-infiltrating cells in the TME.

Tumor-infiltrating cells regulate immunotherapy resistance

Immune cells in immunotherapy resistance

Immunotherapy has demonstrated a significant capacity to manage cancer and provide survival advantages to patients with carcinoma [11, 14]. However, the development of drug resistance hampers the effectiveness of treatment in clinical settings. Various factors influence the response of immunotherapy, such as inflammation [15], senescence [16], hypoxia [17], and so on in the TME. CD8 + T cells occupy a pivotal role in cancer cell management during immunotherapy, and their activity is subject to regulation by many factors [18]. For instance, AXL inhibited the antitumor activity of cytotoxic CD8 + T cells by regulating CD103 + dendritic cells (DCs) migration, T cell priming, and exhaustion in the TME [19]. In pancreatic ductal adenocarcinoma (PDAC), CCL2 enhanced monocyte infiltration and reduced CD8 + T cell infiltration, whereas inhibiting CCL2 expression and neutralizing monocytes could improve immune checkpoint blockade (ICB) therapy efficacy [20]. PTEN is a well-known tumor suppressor gene and is involved in the regulation of drug response [22]. In PTEN loss prostate carcinoma, the PI3Kα/β/δ inhibitor BAY1082439 can enhance CD8 + T cell-mediated immunity, making ICB more effective by promoting activation of the IFNα/IFNγ pathway, increasing β2-microglobulin expression, and boosting secretion of CXCL10/CCL5 [13]. For non-small cell lung cancer (NSCLC), TME with PTEN loss or low expression also exhibited resistance to anti-PD-L1 treatment. Mechanistically, PTEN loss in the TME promoted the differentiation of CD4 + lymphocytes into Tregs through regulating TGFβ and CXCL10 expression [23]. Tregs can create an immune-suppressed TME, reducing the effectiveness of ICB therapy [24]. In cancer patients with liver metastasis, Tregs play a role in systemic immune suppression, leading to resistance against anti-PD-1 therapy. Strategies aimed at depleting or destabilizing Tregs could potentially overcome this resistance and enhance the efficacy of anti-PD-1 therapy [25]. In a cervical cancer study, the NAT10/ac4C/FOXP1 axis in cancer cells modulated reprogramming glycolytic metabolism (increased glycolysis and lactic acid secretion) in the TME. This altered metabolism led to a higher infiltration of Tregs, causing immune suppression and resistance to ICB therapy [26]. Knockdown NAT10 expression significantly improved the efficiency of anti-PD-L1 therapy. In EGFR mutant NSCLC, upregulation of IL-6 was shown to inhibit the anti-tumor function of T and natural killer (NK) cells, while blocking IL-6 could enhance the efficacy of anti-PD-1 therapy [27]. As a new treatment in clinical practice, CAR T cell therapy has acquired wide attention [28, 29]. A few studies reported the role of immune cells in CAR T cell therapy resistance. Venet et al. [30] identified that inhibiting HLA-DR expression in monocyte would result in anti-CD19 CAR T cells failure. Furthermore, the interaction between bone marrow stromal cells (BMSCs) and CAR T cells could reduce resistance against CAR T cells by suppressing apoptosis [31]. The evidence presented underscores the importance of interactions between CD8 + T cells and other T cell subtypes in influencing the efficacy of ICB therapy, emphasizing the need for further research to classify specific T cell subtypes in studies focused on immunotherapy resistance.

In terms of DCs, Vilgelm et al. [32] identified that loss of DCs was the main reason for the resistance of ICB therapy through suppressing the anti-tumor function of CD8 + T cell and CD4 + T cell response. Similarly, a combination of CD40 agonist and ICB therapy effectively induced complete tumor regressions by modulating T cells dependent on CD40 + DCs [33]. Additionally, tumor-secreted miR424 inhibits DC-mediated T cell activation, leading to ICB resistance, which can be overcome by blocking miR424 [34]. DCs have a primary role in antigen presentation, influencing the adaptive immune response and protecting against immunotherapy resistance. NK cells typically exhibit anti-tumor function, but can be modulated by factors like SNORD46 and IGSF8, affecting their cytotoxicity and interaction with cancer cells. In malignant B cells, NK cell cytotoxicity can be suppressed by disrupted ligand binding [35, 36]. In malignant B cells, NK cell cytotoxicity was significantly suppressed by N-glycan-disrupted ligand binding to NK receptors [37]. Of this process, SPPL3 depressed N-glycosylation, which could be recovered by suppressing B3GNT2 expression. Regulation of SPPL3 or B3GNT2 expression maybe a promising way to improve CAR NK cell therapy. Lymphoid cells generally exhibit anti-tumor functions, with exceptions like Tregs. Among these, CD8 + T cells are key effectors in ICB therapy targeting tumor cells, while NK cells play a similar role in CAR therapy. The emergence of resistance to immunotherapy is often due to impaired quantity and function of these cells. Therefore, therapies directly targeting these cells can significantly improve resistance to immunotherapy.

Various myeloid cells play a significant role in influencing the effectiveness of immunotherapy [38]. Of these, TAMs are the main myeloid cells in TME, which have several subtypes [39]. It is usually deemed as a promoter of immunotherapy resistance [40]. M1-TAMs exhibit proinflammatory and phagocytic properties, contributing to anti-tumor responses [41]. Conversely, M2-TAMs display anti-inflammatory characteristics and are involved in wound healing, tumor development, and immune suppression [42]. Platten et al. [43] found that it was innate rather than adaptive immune factors that could predict the response to immunotherapy. Mechanistically, TAMs induced ICB resistance by modulating various pathways, such as the PD-L1/PD-1/CD80 axis, leading to T cell suppression and activation of Tregs in the TME. TAMs also inhibited the anti-tumor function of CD4 + T cells and pro-inflammatory responses via BMP7/P-SMAD1/MAPK14 axis, causing anti-PD1 therapy resistance [44]. Another TAM study found that TREM2 + TAMs were associated with the exhaustion of CD8 + infiltrating lymphocytes and poor recurrence-free survival, while anti-TREM2 mAb therapy could enhance the activation of T cells and sensitize the ICB therapy [45]. Thus, the authors believed that anti-TREM2 mAb therapy may be an alternative treatment for patients with ICB failure. Similarly, JMJD6 in TAMs suppressed TAMs M2 polarization by STAT3/IL-10 axis, inducing anti-PD-1 therapy resistance. In further results, blocking JMJD6 would enhance the efficacy of anti-PD-1 therapy, which identified the importance that exploring the function of different subtypes of TAMs in ICB resistance [46]. Consisted with the above study, M2 TAMs defined by authors created an immune suppressive TME by regulating SPP1/CD44/PI3K/AKT/HIF-1α/CA9 pathway in glioma, promoting the progression of cancer cell and ICB resistance [40]. These findings warrant further investigation into the distinct roles of various TAMs subtypes. Certain TAM subtypes have been recognized for their protective functions in carcinogenesis⁴³. Furthermore, multiple studies have indicated that TAMs can influence the response to ICB through interactions with T cells [43]. Therefore, future research efforts should prioritize unraveling the regulatory mechanisms governing the interplay between TAMs subtypes and T cells, particularly in the context of immunotherapy resistance.

In a study on melanoma, it was found that STAT3 inhibitors could reduce the infiltration of TAMs and MDSCs, thereby enhancing CD8 + T cells in the TME. Further experiments showed that combining a STAT3 inhibitor with anti-PD-1 therapy could overcome resistance to anti-PD-1 monotherapy [47]. Similarly, MDSCs could be recruited through the IKKβ/ARID1A/NF-κB axis, leading to an immune-suppressed TME in prostate cancer. ICB therapy could be re-sensitized when blocking the axis using anti-NF-κB antibody or targeting CXCR2 [48]. MDSCs enhanced pro-angiogenic activity in the TME by secreting BV8, a protein that supports VEGF-independent tumor angiogenesis [49]. Inhibiting BV8 coul reduce MDSC recruitment to the TME, boost cytotoxic T cell efficacy, and overcome ICB resistance33 [50]. These studies suggest that MDSCs may contribute to the promotion of ICB resistance by modulating T cells. In terms of neutrophils, IL17 expression in another PDAC study promoted tumor-related neutrophil (TAN) infiltration and extracellular traps but inhibited CD8 + T cell infiltration. Inhibiting IL17 or neutrophils significantly boosted ICB therapy effectiveness [21]. Disrupting PADI4-dependent NETosis, which phenocopied IL17 neutralization, also impacted ICB therapy sensitivity. Various studies on TANs have indicated that their presence in the TME can lead to resistance to immunotherapy, but inhibiting TAN infiltration or NET formation can restore immunotherapy efficiency [51,52,53,54]. While most myeloid cells may contribute to immunotherapy resistance, exceptions like M1 TAMs exist. These studies emphasize the importance of exploring the specific functions of each immune cell subtype and identifying reliable predictors to determine the need for additional treatments in immunotherapy. Understanding the interactions between CD8 + T cells and other immune cells is crucial for enhancing the efficacy of immunotherapy.

Non-immune cells in immunotherapy resistance

As a stromal cell, TAFs significantly affect the efficiency of immunotherapy [55, 56]. In a PDAC study, authors found that MEK and STAT3 expressed in TAFs induced an immunosuppressive TME by inhibiting recruitment of activated/memory T cells, which caused immunotherapy resistance [57]. Specifically, MEKi + STAT3i treatment in PKT mice reduced proinflammatory and myofibroblastic TAF phenotypes, while increasing mesenchymal-like TAFs. This shift in TAF plasticity drived M2-to-M1 reprogramming of TAMs and enhanced CD8 + T cell trafficking with specific transcriptional activities. These effects were dependent on TAFs, as TAF-targeted MEK1/STAT3 silencing reduced inflammation and myeloid infiltration in vivo. Then, the authors added MEK and STAT3 inhibitors to immunotherapy (Nivolumab) in vivo, which exhibited significantly better clinical benefit compared with using monotherapy alone. Additionally, MFAP5, which encoded microfibril-associated protein 5, influenced extracellular matrix components and functions by modulating TAFs [58]. Bai et al. [59] reported that MFAP5 knockout in TAFs enhanced cytotoxic T cell infiltration through the RCN2/ERK/STAT1 axis by downregulating HAS2 and CXCL10 expression, and remodeled the matrix, synergistically enhancing immunochemotherapy effects in PDAC. In a separate PDAC investigation, TAFs expressing LRRC15 were exclusively located around the tumor tissue and absent from normal pancreatic tissue. The presence of LRRC15 + TAFs was found to be statistically associated with a poor response to immunotherapy [60]. In lung and colorectal cancers, cancer cells increase PD-L1 expression by activating the WNT/b-catenin pathway in bone marrow-derived TAFs, resulting in resistance to immunotherapy [61]. This resistance can potentially be reduced by using WNT inhibitors. In breast cancer, the TAFS/TAF-S1 cluster showed a positive correlation with Tregs, indicating a poor response to immunotherapy [62]. Adenosine is generated by ATP that undergoes rapid stepwise dephosphorylation by ectonucleotidases and can stimulus A2A receptor and A2B receptor to modulate immune activity [63]. In colorectal cancers, CD73 expression in TAFs was mediated by the A2A and A2B pathways. Targeted inhibition of these two pathways has been demonstrated to attenuate immune suppression and augment antitumor immunity in tumors with a high TAFs densit [64].

The evidence presented highlights the importance of TAFs in immunotherapy. Regulating the infiltration of different TAFs is a significant strategy to improve the effectiveness of immunotherapy [65]. Additionally, IFN-γ activated endothelial cells have been shown to suppress CD8 + T cell-mediated immune responses by increasing the expression of PD-L1 and PD-L2 [66]. Lin et al. [67] reported that the number of PD-L1-positive circulating tumor endothelial cells exhibited an incremental trend with prolonged exposure to anti-PD-1 immunotherapy, correlating with a diminished efficacy in progression-free survival in NSCLC. Furthermore, research has demonstrated that BMSCs can induce senescence in CAR T cells through the modulation of IDO-1 activity, IFNγ, and IL-2 release, ultimately weakening the anti-tumor response [68]. These findings emphasize the involvement of non-immune cells in immunotherapy and suggest the need for further exploration. Understanding how stromal cells influence immune cells is crucial, as they can either transform into pro-tumor subtypes that recruit suppressive factors like regulatory T cells or inhibit the recruitment and functions of cytotoxic T cells by secreting pro-tumor factors. The first involves their transformation into pro-tumor subtypes, which leads to the recruitment of suppressive immune regulatory factors like regulatory T cells [57, 62]. The second approach is inhibiting the recruitment and anti-tumor functions of cytotoxic T cells through the secretion of pro-tumor factors or other influences [68]. Given the essential role of cytotoxic T cells in immunotherapy, it is important to focus on researching stromal cells to directly impact cytotoxic T cell function, rather than using indirect methods. Figure 1 illustrates the results of immunotherapy resistance. Figure 1 shows the results of the immunotherapy resistance. Table 1 provides the key references of this part.

Fig. 1

The evolution of infiltration cells contributes to immunotherapy resistance. Exhibiting the interaction between various infiltration cells in tumor microenvironment. Various factors promoted the formation of immunotherapy resistance microenvironment, such as EMT activation, angiogenesis, and metabolism reprogramming. EMT. Tregs: regulatory T cells; MDSC: myeloid-derived suppressor cell; EMT: Epithelial–mesenchymal transition

Table 1 The core references of immunotherapy resistance

Tumor-infiltrating cells induce the resistance of targeted therapy

Immune cells in the resistance of targeted therapy

Targeted therapy, long employed in clinical practice, has extended the survival of cancer patients [69, 70]. However, the emergence of drug resistance has significantly undermined patient outcomes [71, 72]. Recently, researchers have focused on the role of infiltration cells in targeted resistance. TAMs have been found to play a key role in influencing the effectiveness of targeted therapy [73]. For example, in breast cancer, TAMs secreting IL-8 can induce resistance to lapatinib, which can be overcome by using IL-8 inhibitors [74]. In myeloma, the interaction between TAMs and cancer cells, facilitated by iron, can lead to TAMs acquiring a pro-tumor phenotype and inducing resistance to bortezomib [75]. The STAT3 pathway was a core pathway to regulate targeted therapy in TAMs [76]. Mechanistically, TAM-derived exosomes in NSCLC attenuated the anti-tumor function of gefitinib by upregulating the AKT, ERK1/2 and STAT3 pathways, decreasing tumor cell apoptosis. In ovarian cancer, upregulation of STAT3 by PARP inhibitors can polarize TAMs, leading to resistance to PARP blockade [77]. Similarly, overexpression of STAT3 can promote adaptive resistance to gefitinib by inducing M2 TAM polarization in lung cancer [78]. In addition to TAMs, other immune cells are correlated with targeted therapy resistance. NSCLC cell generated IL4/34, activating MDSCs to secrete IL10 and ARG1. These secreting factors suppressed CD8 + T cell function and enhanced the pro-tumor function of Treg cells, ultimately leading to osimertinib resistance [79]. Anti-VEGFR2 therapy facilitated N2-like neutrophil polarization, resulting in CD8 + T cell exhaustion. This exhaustion caused the anti-VEGFR2 therapy resistance in breast cancer [80]. Additionally, in certain cases of breast cancer, the interaction between HLA-G and KIR2DL4 can result in resistance to trastuzumab. Inhibiting this signaling pathway can restore NK cell cytotoxicity and enhance sensitivity to trastuzumab [81]. Based on these results, immune cells within TME markedly affect the efficacy of targeted therapies. However, the absence of identified key regulatory cell types for specific targeted treatments impedes the translation of these results into clinical practice.

Non-immune cells in the resistance of targeted therapy

Senescence can lead to targeted therapy resistance [82, 83]. In melanoma, aged dermal fibroblasts released neutral lipids, particularly ceramides, that enhanced lipid uptake in melanoma cells via upregulated FATP2 expression, leading to resistance to BRAF/MEK inhibitors [84]. Inhibiting FATP2 expression restored melanoma cell sensitivity to these inhibitors, indicating that FATP2 may be a promising therapeutic target. Additionally, PARP inhibitors can induce senescent-TAFs that produce a senescence-associated secretory phenotype (SASP) and become resistant to PARP inhibitor therapy in ovarian cancer. Bepotastine, which blocks the SASP, can reverse drug resistance by inhibiting the histamine H1 receptor-induced NF-κB pathway [85]. Furthermore, STAT3 has been implicated in the resistance of non-immune cells to targeted treatments. In neuroendocrine tumors, TAFs can stimulate cancer cells to upregulate STAT3 expression, leading to resistance to everolimus [86].

In NSCLC, TAFs, extracted from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors-resistance tumor tissues, could produce tryptophan metabolite kynurenine which enhanced the transcription of AHR, inducing the activation of the PI3K/AKT and MEK/ERK pathways. These two pathways created an EGFR tyrosine kinase inhibitors-resistance TME, which could be countered by AHR inhibitor [87]. In gastric cancer, TAFs activate the NF-κB pathway in response to lactic acid secreted by cancer cells. This activation leads to suppression of reactive oxygen species generated by anlotinib in cancer cells through the NF-κB/BDNF/TRKB/KEAP1/NRF2 pathway, promoting anlotinib resistance [88]. In colorectal cancer, TAFs activate the IL6/IL8-JAK2 signaling pathway to promote BRD4 phosphorylation, resulting in resistance to BET inhibitors [89]. TAFs modulated by the TGF-beta pathway also impact the response to cetuximab in head and neck cancer [90]. Additionally, in breast cancer, TAFs contribute to resistance to lapatinib by activating the PI3K/AKT/MTOR and antiapoptotic pathways [91]. Overall, TAFs play a role in inducing resistance to various types of targeted therapies through mechanisms such as senescence and the STAT3 pathway.

In a recent study on lapatinib, researchers found that the interaction between MSCs and TAFs promoted resistance to lapatinib in HER2-positive breast cancer by modulating the PEAK1/INHBA/PI3K/AKT pathway [92]. Similarly, in the bone marrow microenvironment of chronic myeloid leukemia, overexpression of IGFBP-6 or SHH induced an inflammatory microenvironment, facilitating the transition from MSCs to TAFs and conferring resistance to dasatinib [93]. These findings highlight the complex interplay between MSCs and TAFs, suggesting that regulating MSCs to control the resistance-promoting activities of TAFs could be a promising therapeutic strategy. Additionally, in studies on multiple myeloma, MSCs were found to contribute to bortezomib resistance through the CXCL13 pathway [94]. Similarly, in gastrointestinal stromal tumors, MSCs facilitated drug resistance by secreting TGF-β2, which activated the PI3K/AKT pathway and led to poorer patient survival outcomes [95]. Researchers have also discovered that BMSCs play a role in drug resistance. For example, BMSCs induced imatinib resistance in chronic myeloid leukemia by creating a hypoxic tumor microenvironment [96]. Furthermore, BMSCs were found to secrete MMP2, which modified HAPLN1 and activated the NF-κB pathway, resulting in bortezomib resistance in multiple myeloma [97]. In lung adenocarcinoma, BMSCs secreted leptin and IGFBP2 in a hypoxic tumor microenvironment, activating the IGF-1R pathway and leading to erlotinib resistance [98]. BMSCs-induced hypoxia was also observed in the multiple myeloma. Specifically, BMSCs secreted small extracellular vesicles that carried miR-140-5p and miR-28-3p to create a hypoxia TME, resulting in bortezomib resistance [99]. This association between hypoxia, angiogenesis, and the generation of stem cells underscores the multifaceted role of BMSCs in drug resistance mechanisms [100]. Endothelial cells play a central role in angiogenesis and have been shown to impact the effectiveness of targeted therapy [101]. ECs interacted with TAMs to promote angiogenesis in glioblastomas by upregulating the CYP4A/20-HETE/PI3K/AKT pathway [102]. FLA-16, a flavonoid, enhanced vascular normalization by inhibiting CYP4A-mediated VEGF and TGF-β expression through the PI3K/AKT pathway in TAMs and ECs, thus overcoming resistance to anti-VEGF treatment. The mechanism of drug resistance was also reported in another study [103]. Shi et al. [103] demonstrated that tumor cells secreted IGF1, activating IGF1R on ECs and leading to vascular remodeling. This remodeled vasculature supported the proliferation of BRAFV600E kinase inhibitor-resistant tumor cells. Pericytes, in addition to endothelial cells, are also important in angiogenesis, as they secrete TSP-1 and TGFb1 to counteract the effects of BRAFV600E kinase inhibitors [104, 105]. These findings highlight the complex interactions between different stromal cells that warrant further investigation. The infiltration of various cell types can lead to resistance to targeted therapies, emphasizing the importance of identifying specific cellular targets for each therapy to overcome drug resistance. Figure 2 illustrates the specific mechanisms of targeted therapy resistance, while Table 2 provides key references for this section.

Fig. 2

The evolution of infiltration cells contributes to resistance against targeted therapy. The picture specifically describes how different cells (including immune and non-immune cells) generate a therapy-resistant microenvironment via CD4 + and CD8 + T cells inhibition, activating and recruiting regulatory T Cells, and angiogenesis upregulation. MDSC: myeloid-derived suppressor cell; Treg: regulatory T cell; ROS: reactive oxygen species; TAM: Tumor-associated macrophage

Table 2 The core references of targeted therapy resistance

Tumor-infiltrating cells influence chemoresistance

Immune cells in chemoresistance

Chemotherapy, as a primary treatment for many cancers, has greatly improved the outlook for cancer patients. However, the development of chemoresistance hinders the intended survival benefits for patients [106, 107]. In recent years, there have been significant advancements in our understanding of the mechanisms underlying chemoresistance in the TME [108, 109]. Similar to immunotherapy, the activation of STAT3 has been found to influence chemoresistance. For example, STAT3 activation triggered by CCL5 secreted by TAMs can increase the expression of the transcription factor NANOG, leading to chemoresistance [110]. TAM-generated TGF-β1 activated hepatic leukemia factor (HLF) in cancer cells, inducing ferroptosis resistance in triple-negative breast cancer cells by stimulating gamma-glutamyltransferase 1 (GGT1). In response, these cancer cells release IL-6, which promoted further secretion of TGF-β1 by TAMs through the JAK2/STAT3 pathway and finally facilitated cancer progression [111]. Moreover, MDSCs recruited by anaerobic pseudomonas can release IL-23, activating the STAT3-EMT pathway and promoting EMT in tumor cells [112]. In addition to STAT3 regulation, TAMs also influence chemoresistance through various other mechanisms. For instance, oxaliplatin inhibits the differentiation of MDSCs into anti-tumorigenic M1-TAMs, leading to increased migration and invasion of tumor cells [113]. Triptolide inhibits M2-TAM polarization through the PI3K/AKT/NF-kB signaling pathway, thereby suppressing invasion and migration of drug-resistant ovarian cancer cells [114]. The enhanced iron transport in TAMs contributes to tumor progression and chemoresistance [75]. Furthermore, M2-TAMs inhibit TRAF5-mediated necrotic apoptosis in colorectal cancer cells by increasing METTL3-mediated RNA N6-methyladinosine (m6A) modification levels, thereby preventing necrosis [115]. In the context of T cells, colorectal cancer cells were found to secrete CCL20, which subsequently recruited Tregs via the FOXO1/CEBPB/NF-κB signaling pathway, thereby enhancing chemoresistance [116]. As for TANs, IL-1β released by cancer cells treated with chemotherapy was observed to attract TANs and form NETs, ultimately contributing to chemoresistance [117]. Notably, integrin-αvβ1 and metalloproteinase 9, both proteins associated with NETs, were capable of activating TGF-β to induce epithelial-to-mesenchymal transition in breast cancer cells, leading to chemoresistance and metastasis. Furthermore, various studies have shown a positive correlation between TANs or NETs and chemoresistance [54, 118, 119]. NK cells also play a role in chemoresistance, with examples such as IL15-activated NK cells effectively targeting cisplatin-resistant neuroblastoma, thereby overcoming chemoresistance [120]. Moreover, therapy involving helminth-derived Taenia crassiceps combined with 5-fluorouracil was found to enhance NK cell recruitment and cytotoxic activity, ultimately improving chemotherapy efficacy [121]. These findings underscore the significance of NK cells in combating chemoresistance. In contrast to the impact of immunotherapy, T cells do not seem to play a significant role in chemotherapy, as evidenced by studies highlighting distinct treatment mechanisms. When compared to resistance to immunotherapy, TAMs, NK cells, MDSCs, and TANs exhibit similar functions in mediating chemoresistance. Notably, two studies have specifically addressed the role of M2-TAMs in chemoresistance, serving as valuable references for future investigations.

Non-immune stromal cells in chemoresistance

Non-immune stromal cells within the TME play a role in chemoresistance [122]. For example, TAFs secrete the lncRNA CCAL, which interacts with the mRNA-stabilizing protein human antigen R to activate the Wnt/β-catenin pathway in colorectal cancer cells, leading to chemoresistance [123]. Similar to regulating the CXCR4/Wnt/β-catenin pathway, CXCL12, derived from TAFs, could trigger EMT in epithelial ovarian cancer cells to resist cisplatin [124]. Exosomes facilitate communication between different cell types, with TAFs secreting exosomes that contribute to the TME. These exosomes may contain miR-522, which inhibits ferroptosis in cancer cells by targeting ALOX15, thereby promoting chemoresistance in gastric cancer [106]. In prostate cancer, TAFs secrete exosomal miR-423-5p, which promotes chemoresistance by targeting GREM2 through the TGF-β signaling pathway [125]. Moreover, in pancreatic ductal adenocarcinoma (PDAC), the knockout of IL-6 in α-smooth muscle actin (αSMA) + TAFs can enhance the effectiveness of gemcitabine treatment and improve survival rates [126]. Metastatic lymph TAFs have been shown to regulate the p38 and JNK signaling pathways by secreting PI16, ultimately reducing cisplatin-induced apoptosis in esophageal squamous cell cancer cells [127].

Similar to TAFs, MSCs also play a role in modulating cisplatin resistance. When treated with leptin, MSCs can upregulate TGF-β, leading to increased expression of autophagy-related genes such as ATG7, ATG5, and beclin1, ultimately inducing cisplatin resistance in osteosarcoma cells [128]. Additionally, MSCs in the tumor microenvironment of glioma can migrate to glioma cells through guidance from angiogenic cytokines. These migrated MSCs can enhance FOXS1 expression in glioma cells by secreting IL-6, triggering EMT and promoting resistance to temozolomide [129]. Downregulation of METTL3 in MSCs would lead to an increase in AKT protein levels which promoted MSCs adipogenesis, resulting in chemoresistance in acute myeloid leukemia cells [130]. MSCs can also interact with leukemia blasts, activating ABC transporters and facilitating the transition of acute myeloid leukemia cells into a more chemoresistant subset [131]. By secreting CXCL13, MSCs can upregulate the expression of BTK, NF-κB, BCL-2, and MDR-1 mRNA and protein, thereby enhancing the resistance of multiple myeloma cells to bortezomib [94]. The findings suggest that mesenchymal stem cells (MSCs) can play a role in promoting chemoresistance, including in endothelial cells. In glioblastoma, CCBE1, an extracellular matrix protein, stimulated hyper-angiogenesis and partial endothelial-to-mesenchymal transition in human microvascular ECs via the VEGFC/RHO pathway, conferring temozolomide resistance to cancer cells. Mechanistically, SP1 upregulated CCBE1 expression in temozolomide-resistant cells. CCBE1, aided by CAVIN1, was then secreted into the TME, promoting VEGFC maturation through the VEGFR2/VEGFR3/RHO pathway in vascular ECs, thus enhancing abnormal angiogenesis in temozolomide-resistant tumors [132]. The transformation of endothelial cells into mesenchymal stem cell-like cells was also observed in another study on glioblastoma, where the C-MET/WNT/β-catenin/MRP1 pathway was implicated in inducing temozolomide resistance [133]. Two separate studies reported an increase in angiogenesis in chemoresistant tumor tissue. Bone marrow-derived mesenchymal stem cells (BMSCs) were found to induce bortezomib resistance through the generation of HAPLN1 and MMP2, which activated NF-κB signaling [97]. Disrupting gap junctions between acute myeloid leukemia cells and BMSCs using carbenoxolone was shown to impair energy metabolism in tumor cells and reduce chemotherapy resistance [134]. The complex regulatory pathways through which non-immune stromal cells impact chemotherapy resistance present challenges for clinical experimentation. Moreover, the lack of classification of these cell subtypes in the studies mentioned detracts from their overall value. Specific mechanisms are detailed in Fig. 3, while Table 3 provides key references on chemoresistance.

Fig. 3

Chemotherapy-induced hypoxia, vascular damage, and chronic inflammation are associated with the development of chemoresistance. Various infiltration cells in the TME play crucial roles in contributing to chemoresistance. Various factors promoted the formation of chemoresistance microenvironment, such as STAT3 pathway activation, EMT activation, and TAFs secreted pro-tumor exosomes. MDSCs: myeloid-derived suppressor cell; Tregs: regulatory T cells; MSCs: mesenchymal stem cells; BMSCs: bone marrow stromal cells; TAFs: Tumor-associated fibroblasts.; TAM: Tumor-associated macrophage

Table 3 The core references of chemoresistance

Tumor-infiltrating cells in radiotherapy resistance

Radiation therapy (RT) is an essential treatment for almost all types of cancer [135]. However, the challenge of radio-resistance remains, leading to issues such as treatment failure, tumor spread, cancer recurrence, and ultimately, a poor prognosis [136, 137]. In oral squamous cell carcinoma, cancer cells thriving in an acidic microenvironment acquire characteristics of EMT and develop resistance to radiotherapy [138]. Radiotherapy works by directly damaging and killing tumor cells through DNA damage and releasing neoantigens into the immune system. In colorectal cancer, the combination of PD-L1 + immune cells and budding nucleus β-catenin + tumor cells can create a niche lesion for cancer stem cells, resulting in resistance to neoadjuvant chemoradiotherapy [139]. The inhibition of the DNA damage repair pathway with AZD6738 has been shown to enhance the effectiveness of radioimmunotherapy for hepatocellular carcinoma by recruiting CD8 + T cell infiltration [140]. In liver cancer, inhibiting MELK promotes TAMs M1 polarization and CD8 + T cell infiltration, while blocking TAMs M2 polarization through the secretion of STAT3-derived CCL2 enhances RT efficiency [141]. Similarly, the expression of TMEM160 in colorectal cancer cells can reduce RT sensitivity and CD8 + T cell activity by downregulating PD-L1 degradation, with downregulation of TMEM160 expression leading to the restoration of RT sensitivity [142]. Various studies have also highlighted that the suppression in number and function of CD8 + T cells is a significant factor in RT resistance, with the activation of CD8 + T cells being able to overcome this resistance [143,144,145]. In terms of Tregs, glioblastoma models treated with RT tend to recruit CD103 + Tregs, resulting in RT resistance and a decrease in CD8 + T cell activity [146]. Depletion of CD103 + Tregs has been shown to restore the efficacy of RT. The role of T cells is crucial in immunotherapy, chemoresistance, and RT. In breast cancer, researchers have found that mebendazole can enhance NK cell-mediated cytotoxicity against cancer cells, thereby improving the efficacy of RT [147]. Another study indicated that combination of RT and injection exogenous NK cells could significantly improve RT efficiency in vitro and in vivo [148]. In terms of TAMs, it was observed that miR-143-3p released by esophageal squamous cancer cells promoted TAM M2 polarization, resulting in RT resistance [149]. Furthermore, Ma et al. [150]. reported that engineered M1 macrophage-derived exosomes could enhance cancer cell DNA damage, polarize M2 macrophages into M1 phenotypes, and recover T cell anti-tumor function, consequently improving RT efficiency. Similarly, TANs and NETs would lead to RT resistance [151, 152]. For example, GLUT1 expression in TANs could facilitate glucose uptake, reducing RT efficiency in lung cancer, while inhibiting GLUT1 could restore RT sensitivity by decreasing glucose uptake in TANs [153]. Overall, RT resistance is influenced by various factors, and understanding the molecular mechanisms of radiation tolerance and its interaction with the tumor microenvironment has the potential to enhance the effectiveness of radiation therapy [148]. It is important to recognize that RT resistance is often associated with RT-induced alterations in the immune microenvironment. Anti-tumor lymphoid cells such as T cells and NK cells have the potential to overcome this RT resistance, presenting a promising approach to improving RT efficacy. Therapeutically, modulating the quantity and function of immune cells within the tumor microenvironment through pharmacological interventions or supplementing therapy with exogenous immune cells could enhance RT outcomes.

Furthermore, stromal cells in the TME can also affect RT resistance. TAFs have been identified as key mediators of RT resistance through various mechanisms [154]. For example, TAF-conditioned media has been shown to enhance RT resistance in NSCLC cells by activating the SMAD3/ITGA6/PI3K/AKT pathway [154, 155]. In esophageal squamous-cell carcinoma, TAF-derived collagen type 1 promotes DNA damage repair and induces RT resistance, while cancer cell-secreted CXCL1 further exacerbates this resistance [156]. Interestingly, the reciprocal interaction between cancer cell-secreted CXCL1 and TAFs leads to increased RT resistance through the CXCL1-CXCR2 pathway. In nasopharyngeal carcinoma, TAFs have been found to reduce irradiation-induced DNA damage and promote RT resistance via the IL-8/NF-κB pathway [157]. To solve TAF-induced RT resistance, Jian et al. [158]. created a nanoplatform to clear TAFs and senescent TAFs (which also could induce RT resistance), obviously improving RT resistance. In terms of MDSCs, RT promoted MDSCs infiltration and YTHDF2 expression, resulting to RT resistance [159]. Mechanistically, knockout YTHDF2 in myeloid cell would change MDSC differentiation and attenuate MDSC infiltration and function by activating the NF-κB pathway, recovering RT sensitivity of cancer cells. In pancreatic cancer, tumor cells secrete lactate, promoting the infiltration of an immunosuppressive MDSC phenotype, leading to resistance to RT [160]. Of these, HIF-1α was the essential of lactate-induced resistance by mediating the GPR81/mTOR/HIF-1α/STAT3 pathway, while inhibiting lactate generation or HIF-1α depletion in MDSCs would recover T cell anti-tumor function and thus overcome RT resistance. Similarly, several studies also found that the pro-tumor MDSC subtype facilitated RT resistance by interacting with cancer cells or immune cells [161,162,163]. Regarding ECs, depression of DAB2IP in breast cells would induce RT resistance by promoting angiogenesis [164]. Moreover, reducing STAT3 in breast cancer cells with decreased DAB2IP expression has been found to enhance RT sensitivity by suppressing angiogenesis. This research suggests that stromal cells have the ability to influence cell differentiation and modify the TME by promoting processes like angiogenesis or metabolic changes through interactions with cancer cells, such as repairing RT-induced DNA damage, ultimately leading to RT resistance [159, 160]. While some studies have indicated that certain stromal cells can differentiate into anti-cancer subtypes, there is a lack of research on the specific classification and functions of these subtypes, indicating a need for further investigation.

Antiandrogen therapy resistance is widely observed in clinical practice. Sawyers et al. [165] discovered that NRG1 in TAF supernatant activated HER3 on prostate cancer cells, leading to antiandrogen resistance. Inhibiting the NRG1/HER3 axis could resensitize tumors to androgen deprivation therapy both in vitro and in vivo. Further investigation is needed to fully understand the intricate mechanisms at play. Table 4 in this study serves as a comprehensive reference guide of this section.

Table 4 The core references of radiotherapy resistance

Conclusion and perspective

The significant challenge of anti-tumor drug resistance poses a considerable obstacle to effective cancer management and the successful implementation of precision medicine. Therapies targeting the TME may offer a valuable strategy to mitigate drug resistance, with factors such as inflammation, metabolism, senescence, hypoxia, and angiogenesis playing key roles in modulating drug resistance through interactions among various cell types. STAT3 and its pathways are crucial in different therapies and cell types within the TME, with evidence showing that STAT3 enhances ICB resistance and cell polarization, while its inhibition can reverse drug resistance. In chemotherapy, inhibiting STAT3 expression can alleviate chemoresistance, and in targeted therapy, overexpression of STAT3 is linked to drug-resistant cancer or stromal cells. Given the potential of targeting STAT3 to combat cancer therapy resistance, future research should focus on this pathway in the context of TME drug resistance. Clinically, STAT3 expression could be used as an indicator to predict response to adjuvant therapy, and STAT3 inhibitors show promise as effective anti-resistance treatments in cancer management.

Distinct subtypes such as CD8 + T cells, Tregs, and CD4 + T cells are defined within T cells, enabling focused research on their individual roles in therapy resistance. However, clear definitions of subtypes for many immune and non-immune cell types remain uncertain. While some studies have attempted to classify these subtypes, widespread acceptance and application have not been achieved. Furthermore, current research often emphasizes the overall impact of stromal cells on therapy resistance, rather than specific subtypes, leading to reduced statistical robustness and specificity in these studies. Current evidence highlights the anti-tumor functions of specific subsets of stromal cells, such as TAFs and TAMs [166]. Accordingly, future research should address this issue by aiming to provide high-quality evidence. Despite existing limitations, we assert that approaches targeting the TME to overcome therapy resistance hold promising and valuable potential.