In this initial stage of cancer immunoediting, many anti-tumor immune subsets, including T cells, B cells, innate lymphoid cells (ILCs), such as NK cells and NKT cells, and M1-type macrophages, destroy cancer cells by invading the tumor sites in response to molecular signals (11, 12).

Since T cells are one of the largest subsets in the TME and primarily contribute to TILs, they have been the subject of extensive research (13). Both the antitumor response and the invasion of the TME depend on them. Numerous signaling molecules, including chemokines (e.g., CCL3, CCL4, CCL5, CCL20, CXCL9, CXCL10, CXCL11, and CXCL16) and their receptors, cause infiltration into the TME (14–17). In head and neck cancer, MHC-I molecules display antigens to TCRs, which in turn activate cytotoxic T lymphocytes to specifically attack tumor cells and trigger their apoptosis (18, 19).

Death receptor ligation, FASL, TRAIL, and the release of granzyme B and perforin can all trigger apoptosis ( Figure 3 ) (20). Naïve CD4⁺ T cells, when activated by tumor antigen-primed APC and exposed to various cytokines, can differentiate into different subsets, such as T-helper cells: Th1, Th2, Th9, Th17, Th22, and T-regulatory (Treg) cells (21, 22). Th1 cells secrete interleukin-2 (IL2) and interferon-γ (IFNγ) to aid in CTL activation. IFNγ plays a crucial role in inhibiting tumor growth, enhancing MHC expression, and limiting angiogenesis in cancers such as brain tumors, melanoma, and colon cancer (23–25). Th2 cells release cytokines like IL4 and IL13, which can induce eosinophil recruitment into the TME (26). CD4⁺ T cells, together with immune partners like DCs, B cells, and NK cells support cytotoxic T cells in carrying out their effector functions; (27–29). Evidence indicates that Th1 cell differentiation and function are closely related to those of other immune cells in the TME. For example, it has been demonstrated that DCs, M1 macrophages, and B cells promote Th1 cell development by generating cytokines such as IL12 and IFNγ (30–32).

According to a recent analysis, Th9 cells in the TME of solid tumors are linked to a strong anti-tumor immune response via both innate and adaptive immunological pathways (33). Th9 cells primarily rely on IL9 and IL21 to perform their anti-tumor function. CCR6⁺ DC and CCR6⁺ CD8⁺ T cells are drawn into the tumor bed and have a higher chance of surviving when IL9 stimulates epithelial lung cells to generate CCL20 (34). IL21 from Th9 cells stimulates CD8⁺ T cell proliferation and boosts NK cytolytic activity and IFNγ production (34). Recombinant IL9 activation increased the cytotoxicity of tumor-specific mice CD8⁺ T cells, whereas blocking IL9-signalling decreased the production of granzyme B and perforin in human CD8⁺ T cells (35). In a murine model, studies showed that a reduction in tumor-specific Th17 cells facilitated the advancement of B16 melanoma, with this effect directly associated with the production of IFNγ. Martin-Orozco et al. provide solid evidence that Th17 facilitates the activation of tumor-specific CD8⁺ T cells, hence indirectly inhibiting tumor growth (36, 37). Th17 cells possess the ability to acquire Th1-like characteristics and secrete substantial amounts of IFNγ, likely enhancing anticancer immune responses (38, 39). DCs release IL12, which promotes CD4⁺ T cells to develop into Th1 cells and triggers a strong Th1 immune response (40). Memory T cells may stay in pathogenic tissue, as in the case of resident memory T (TRM) cells, or they may circulate in the immune system to react quickly and strongly to subsequent exposure to antigens (41).

Similar to CTLs, NK cells induce apoptosis in tumor cells by releasing cytolytic granules that include granzymes and perforins ( Figure 3 ) (20). Table 1 lists examples of activating and inhibitory receptors present on NK cells and NKT cells. Natural killer group-2 member-D (NKG2D), DNAX accessory molecule-1 (DNAM-1), NKp30, NKp44, and NKp46 are some of these activating receptors. Activating receptors use an immunoreceptor tyrosine-based activation motif (ITAM) located on their cytoplasmic tail to transduce signals. NKG2D is also expressed by NKT cells, CD8⁺ αβT cells, and γδ T cells (20, 54). As a result of signal transduction triggered by NKG2D receptor-ligand interaction, the tumor cells are degranulated by NK cells. While activating receptors initiate cytolytic activity, inhibiting receptors, such as those that detect MHC-I, limit their ability to kill normal, healthy cells (54, 55).

NKT cells are a subset that is characterized by their dual roles. They express αβ-TCR to identify endogenous and foreign lipid antigens presented on CD1d, a non-classical antigen-presenting protein resembling MHC class-I. On the other hand, they show NK cell characteristics due to the expression of CD56, CD16, and Fc receptor on their surface and granzyme production (15, 56). Leukocyte function-associated antigen-1 (LFA1) expression, CCR2, and CXCR6 can all mediate the recruitment of NKT cells (20, 56). NKT cells release Th1 and Th2 cytokines, including IFNγ, tumor necrosis factor-α (TNFα), IL2, IL4, IL5, IL6, IL10, IL13, IL17, IL21, transforming growth factor-β (TGFβ), and granulocyte monocyte-colony stimulating factor (GM-CSF), upon activation via αβ-TCR and CD1d interaction (57).

B cells are vital for their antigen-presenting capability since B cell receptor (BCR) is far more specific to antigen recognition than the other APCs (58). In the TME, B cells act in multiple ways. They increase the density of T cells in the tumor by activating CD4⁺ T cells. They also mediate the conversion of CD4⁺ T cells and CD8⁺ T cells into distinct functional subsets (59). B cells can modulate the activity of other APCs, such as DCs and macrophages, enhancing their ability to present antigens effectively (58, 60, 61). A “helper” function for B cells in the tumor immune response is that activated CTLs can interact with soluble CD27 produced by CD19⁺ B cells, which promotes their survival and proliferation (62). The discovery that IgG2b-mediated activated B cells were highly lethal to tumor cells raised the possibility that B cells also contributed to the inhibition of tumor growth (63). Additionally, pulmonary host B cells were found to enhance IFNγ production and facilitate NK cell killing of tumor cells, suggesting that effector B cells may have a protective role against cancer (64, 65). CD20⁺ B cells recruit CD8⁺ T cells by the production of chemokines such as CCL3, CCL4, CCL5, CXCL10, and CXCL13. CXCL13 is a major chemokine that recruits B and T cells to malignancies (66–68). By stimulating T-cells, particularly CD4⁺ T cells, B cells improve the density and responsiveness of T cells in the TME (59).

Type-1 macrophages (M1) have anti-tumor characteristics that allow them to distinguish between transformed and healthy cells. The way by which M1-type macrophages eliminate tumor cells after identifying them has been demonstrated to be impacted by two different factors (69). Using a variety of mechanisms, M1-type macrophages directly mediate cytotoxicity to kill tumor cells (70). One of the ways they achieve this is by generating molecules that kill tumors, such as ROS and NO, which have a cytotoxic effect on tumor cells (71) ( Figure 4 ). The second pathway, known as antibody-dependent cell-mediated cytotoxicity (ADCC), kills tumor cells by selectively targeting them using anti-tumor antibodies (72). The destruction of tumor cells by NK cells is improved when Dectin1 is expressed on M1 macrophages (69). By secreting large amounts of pro-inflammatory cytokines IFNγ and IL12, which have anti-tumor activity, M1 macrophages incite NK cell and cytotoxic T cell infiltration and activation in the tumor site, indicating an indirect mechanism of stopping the spread of cancer (69, 73) ( Figure 4 ).

The subsequent phase of cancer immunoediting, referred to as the equilibrium phase, occurs when tumor cells undergo continuous reshaping to increase their resistance to immune effector cells (74). Immune selection promotes tumor cells with lower immunogenicity as a result of this strategy. The paradox of tumor growth in an immunocompetent individual may be answered with the emergence of highly evolved resistant cancer cells (1, 2). Although these tumor cell variations are less immunogenic, random genetic changes inside tumor cells may result in more unstable malignancies. Nucleotide-excision repair instability (NIN), microsatellite instability (MIN), and chromosomal instability (CIN) are the three forms of genetic instability linked to cancer that have been suggested to be the cause of the “mutator phenotype” of tumor cells (74). Moreover, immune selection pressure increases the likelihood of tumor cell clones with a non-immunogenic phenotype (1, 3).

Of the three stages of cancer immunoediting, the equilibrium phase is probably the longest and may continue for many years (1, 74). It entails the constant removal of tumor cells and the emergence of resistant tumor variants as a result of immune selection pressure. It is unclear how exactly TILs and TAMs contribute to preserving equilibrium, even though their function in the elimination and escape phase has been thoroughly investigated. Research has shown that adaptive immunity components CD4⁺ T cells, CD8⁺ T cells, IL12, and IFNγ are in charge of keeping tumor cells in balance by exerting immune selection pressure ( Figure 3 ) (1, 2). This Darwinian selection phase destroys many of the original tumor variants while tumor variants with distinct mutations that boost resistance to immune attack survive and proliferate to reach the next phase (1, 74). Moreover, the relative balance between effector and regulatory immune cells is also considered to be the most important factor in this phase (75). Additionally, studies showed that tumors remain in an equilibrium condition when IL12, which promotes elimination, and IL23, which promotes persistence, are balanced (76). Besides this, Th1 to Th2 cytokine bias also plays a very important role in maintaining the tumor in this phase (77, 78). By decreasing the activity of anti-tumor immune cells, anti-inflammatory cytokines such as IL10 and its expression level play a significant role in the equilibrium phase and cause the tumor to enter the escape phase (79).

In the escape process, the surviving tumor variants that bypass the immune detection and elimination start to proliferate in an uncontrolled manner and employ various mechanisms to create an environment for their survival (80). In this phase, tumor-promoting immune cells like Treg cells, Breg cells, and M2-type TAMs infiltrate the tumor and promote tumor growth by suppressing the function of anti-tumor immune subsets (69, 81). In addition, Th1 to Th2 cytokine bias is also considered an important factor that maintains the tumor in an equilibrium phase. Immunosuppressive cytokines like IL10 and its expression level determine the shift from equilibrium to the escape phase.

Tumor cells downregulate MHC class-I to evade CTL-mediated death by impairing their ability to process and deliver antigens (19). Additionally, tumor cells frequently exhibit dysregulated expression of death receptors like FAS and/or upregulate anti-apoptotic molecules like BCL2. TH2 cells secrete IL4, IL5, IL10, IL13, and IL17 - all of which have been shown to contribute to the tumor-promoting role of this subtype, even though IL4, IL5, and IL13 have been shown to contribute to the growth and metastasis of cancer (82, 83). CD4⁺ Th2 cells encourage the growth of tumors by suppressing Th1 cell-mediated immunity and boosting angiogenesis (84). However, recent literature has reported that IL10 has a dual pro- and anti-tumorigenic role (85, 86). IL10 elicits an anti-inflammatory immune response, downregulates Th1 cytokine function, and MHC class-II antigen presentation (87). At the same time, binding of IL10 with its cognate receptor activates signal-transducer and activator of transcription-3 (STAT3)-signaling and transcription of anti-apoptosis and cell cycle progression genes, further strengthening the pro-tumorigenic effect (88). Greater IL9⁺ cell infiltration in the tumor tissue was associated with worse prognosis, greater frequencies of Treg cells, and decreased cytotoxic capability of CD8⁺ T cells and NK cells in patients with muscle-invasive bladder cancer (89). The main issue with the Th9 function in the TME is that different tumor types exhibit inconsistent behavior.

One essential cytokine that controls the activity of mast cells and Treg cells is IL9. Feng et al. found that in B-cell non-Hodgkin’s lymphoma (NHL), IL9 was associated with immunosuppression mediated by CD117⁺ mast cells and FOXP3⁺ T-regulatory cells (90). Additionally, studies showed that Th9 cells enhanced the phosphorylation of STAT3, which has been linked to a poor prognosis for patients with HCC, hence increasing the production of CCL20. CCL20 is known to stimulate the migration and proliferation of tumor cells (34, 91). Th17 cells have two functions in the TME. This cell subgroup inhibits anti-cancer responses by producing immunosuppressive adenosine, and promotes angiogenesis as well as tumor development by releasing pro-inflammatory IL17A (92). The TME may encourage Th17 cells to differentiate into suppressive Treg cells, which would aid in immunosuppression (37, 93). Compared to the density of Th17 cells in the patient’s surrounding, non-tumor tissue, a noticeably higher number of Th17 cells infiltrate malignancies. This increased Th17 cell presence in tumor tissue is consistent across a wide spectrum of cancers, suggesting that tumors themselves generate components that facilitate Th17 cell trafficking to the site of illness (94). Th17, along with Th2, are involved in chronic inflammation, which encourages the growth and development of tumors (37, 84).

To avoid immune surveillance by NK cells, tumor cells downregulate their surface ligands, thereby obstructing anti-tumor recognition. TGFβ, IFNγ, STAT3, hypoxia, proteolytic shedding, the generation of soluble ligands, and certain microRNAs collectively facilitate the downregulation of ligands (95–97). Cancer cells release immunosuppressive microvesicles, such as exosomes, that display NKG2D ligands (NKG2DLs) on their surface. These ligands bind to NKG2D receptors on NK cells and CD8⁺ T cells, leading to receptor downregulation, internalization, or degradation. This decoy interaction prevents NKG2D from recognizing tumor-expressed ligands, reducing tumor detection and impairing the anti-tumor activity of NK cells and CD8⁺ T cells (95, 98, 99).

T-regulatory cells, characterized by their immunosuppressive properties, infiltrate the TME via four distinct mechanisms. Initially, by transitioning to the TME from the circulatory or lymphatic systems. Signaling molecules such as chemokines and their receptors (e.g., CCL1-CCR8, CCL5-CCR5, CCL22-CCR4, CCL28-CCR10, and CXCL12-CXCR4) facilitate the ingress of Tregs into the TME (17, 100, 101). Secondly, immunosuppressive chemokines and cytokines can enhance their development in the TME. Third, by the expansion mediated by DC activation. Ultimately, effector T cell differentiation into Treg cells by TGFβ (102). CD25⁺ and FOXP3^lo Treg cell progenitors are the origins of thymically mature Tregs (101, 103). Tregs facilitate tumor growth and metastasis when they are recruited to the TME. Various suppressive functions of Treg cells are facilitated by immunosuppressive cytokines secreted by Tregs, such as TGFβ, IL10, and IL35 ( Figure 3 ) (103). Treg cells can restrict the activity of antigen-presenting cells by downregulating the expression of CD80 and CD86 in a CTLA4-dependent way, therefore preventing the presentation of tumor antigens and the activation of tumor-specific T cells (104). Since an almost total suppression of CD8-mediated cytolytic activity is primarily reliant on TGFβ-signaling, and CD8⁺ T cells with a dominant negative TGFβ receptor were resistant to this suppression, and CD8⁺ T cells with a dominant negative TGFβ receptor were resistant to this suppression, TGFβ secretion from Treg cells can regulate CTL function and reduce anti-tumor immunity (105).

Previous findings indicate that Treg cells inhibit the proliferation and functionality of CD4⁺ and CD8⁺ T cells by depleting available IL2 and activating IL2/IL2-receptor signaling (101, 106). A recent study investigating the antigen specificity of Treg cells across several malignancies revealed that intra-tumoral Treg cells selectively responded to tumor antigens, leading to the activation and clonal expansion of Treg cells (107). Treg cells inhibit the interactions between antigen-presenting cells and T cells, hence obstructing the maturation and functionality of APCs, which subsequently impedes the activity of effector T cells (108, 109). Furthermore, Treg cells diminish the efficacy of NK cells. Treg cells can suppress anti-tumor immunity by diminishing responses from both the innate and adaptive immune systems (110, 111). T-regulatory cells are associated with a low survival probability in cancer patients (112, 113).

Numerous studies indicate that Breg cells infiltrate human malignancies and suppress anti-tumor immune responses through the expression of immune checkpoint molecules (PDL1) and immunosuppressive cytokines (IL10, IL35, and TGFβ) ( Figure 3 ) (114, 115). Additionally, a significant presence of Breg cells was observed to diminish antibody-mediated humoral immunity in cancer patients (115). The effector molecules of Breg cells, such as TGFβ, IL10, and IL35, can diminish effector T cell responses and/or promote Treg differentiation, thereby resulting in enhanced tumor progression (116). Breg cells impede the development of naïve T cells into Th1 and Th17 (117). They also exert analogous effects on dendritic cells and macrophages (117). Advanced hepatocellular carcinoma, gastric carcinoma, and prostate carcinoma often exhibit elevated levels of Breg cells, indicating that Breg cells may influence tumor development and metastasis (118–120). Breg cells secrete cytokines such as TGFβ, which can convert M1 macrophages into an M2 immunosuppressive phenotype and induce the differentiation of naive CD4⁺ T cells into Treg cells, leading to remodeling of the TME (121, 122).

The growth of the tumor is closely associated with macrophage infiltration. Multiple studies have shown that tumor-associated macrophages can secrete various cytokines, such as platelet-derived growth factor (PDGF), TGFβ1, hepatocyte growth factor (HGF), epidermal growth factor (EGF) family, and basic fibroblast growth factor (BFGF), that facilitate tumor cell proliferation and survival (123). Another study indicates that the malignant invasion of phyllodes tumors is facilitated by a positive feedback loop of CCL5 and CCL18 between TAM and myofibroblasts. CCL5 triggers the AKT-signaling upon binding to its receptor to attract and repolarize tumor-associated macrophages. Consequently, TAMs secrete CCL18, which promotes the invasion of malignant tumors by converting mesenchymal fibroblasts into myofibroblasts (124). M2 macrophages can enhance the migration of tumor and stromal cells by secreting matrix metalloproteinases (MMPs), cathepsins, serine proteases, and various collagen types, along with other extracellular matrix components, which degrade the endothelial cell matrix membrane to facilitate neo-angiogenesis (70). The secreted factors promote epithelial-mesenchymal transition (EMT), resulting in tumor spread (125). In addition to synthesizing angiogenic factors, macrophages can express many enzymes that regulate angiogenesis, including MMP-2, cyclooxygenase-2, MMP-7, MMP-9, and MMP-12 ( Figure 4 ) (70, 126). M2 macrophages secrete immunosuppressive cytokines that promote the Th2 response, whereas M1 macrophages elicit the Th1 response through the production of pro-inflammatory cytokines (127). TAM-derived TGFβ has been shown to induce HIF1/TRIB3-signaling, hence facilitating the advancement of cancer (128).

Tumor-associated macrophages produce large amounts of the immunosuppressive cytokine IL10, which inhibits the cytotoxic activity of Th1 cells, NK cells, and CD8⁺ T cells against tumor cells (129). This constrains the TME’s capacity to inhibit tumor growth. The recruitment of Tregs to the TME through the chemokine receptor CCR4 is significantly enhanced by tumor-associated macrophage-derived CCL17/CCL22 (17) ( Figure 4 ). Reports indicate TAM-mediated Treg recruitment in liver, nasopharyngeal, and ovarian malignancies. These Tregs suppress anti-cancer CTL activity (130). M2-TAMs preserve their immunosuppressive characteristics and effectively deplete the anti-tumoral immune response by exhibiting elevated synthesis of immune checkpoint inhibitor (ICI) PDL1 and cytotoxic T-lymphocyte antigen-4 (CTLA4) ligand (69). The TGFβ and IL10 generated by TAM hinder the maturation and proliferation of DCs. Consequently, antigen presentation diminishes, leading to a compromised adaptive immune response (69, 131) ( Figure 4 ).

A key element influencing the success of immunotherapy lies within the TME, particularly the presence and characteristics of tumor-infiltrating lymphocytes and tumor-associated macrophages. Biomarkers associated with these immune cells serve as important predictors of treatment response. For instance, a high density of TILs, especially CD8⁺ T cells, has consistently been linked to improved clinical outcomes across multiple cancer types (192). Recent clinical analyses reveal that elevated levels of intratumoral tissue-resident memory T cells (TRMs), characterized by CD103⁺ and CD69⁺ expression, correlate with better responses to immune checkpoint inhibitor therapies in non-small cell lung cancer and oral cancer (193).

Markers indicative of T cell exhaustion, including TIM3, CTLA4, and PD1, reflect impaired T cell function and significantly impact the effectiveness of checkpoint blockade treatments (193). In melanoma patients treated with anti-PD1 therapy, the proportion of precursor exhausted T cells (TPEX cells) has been associated with longer-lasting responses, underscoring their potential as predictive biomarkers (193, 194). Furthermore, the presence of tertiary lymphoid structures (TLS), organized aggregates of B cells, DCs, and T cells, has been linked to enhanced therapeutic responses in ICIs-treated soft tissue sarcoma and melanoma patients (195, 196). Conversely, elevated FOXP3 expression, a marker for Treg cells, is often associated with immunotherapy resistance, immunosuppression, and poorer prognoses (197).

On the macrophage front, molecules expressed by different TAM subsets also play a critical role in shaping immunotherapy outcomes. M1 macrophages, known for their pro-inflammatory and anti-tumor functions, typically express markers such as CD80, CD86, and IL12. In contrast, M2 macrophages, which tend to support tumor progression and immune suppression, are characterized by markers including CD163, CD204, CD206, and IL10 (198). The ratio of M1 to M2 macrophages within the tumor has been linked to both patient survival and response to immunotherapy in cancers such as breast cancer (199). Additionally, high expression levels of TAM infiltration markers like CD68 and CD163 have been correlated with poor prognosis and treatment resistance in cervical and oral squamous cell carcinomas (200, 201). Together, these biomarkers provide valuable insights into the immune landscape of tumors and help guide personalized immunotherapy approaches for improved patient outcomes.

In the foreseeable future, immune checkpoint inhibitor therapy will predominate in cancer treatment (202–204). Neglecting immunophenotyping prior to the initiation of checkpoint inhibitor therapy may accelerate tumor progression (205). As a result, immunophenotyping contributes significantly to cancer research by revealing the immune landscape of tumors and supporting the design of targeted and personalized treatment strategies for diverse immunophenotypes, ultimately enhancing the efficacy of checkpoint inhibitor treatments.

Immunotherapy outcomes can vary widely even among patients diagnosed with the same type of cancer, and one of the key factors influencing this variability is the composition of tumor-infiltrating immune cells within the TME. Tumors are often classified as “hot” or “cold” based on their immune cell infiltration profiles. “Hot tumors” are characterized by a TME rich in tumor-infiltrating lymphocytes, particularly CD8⁺ T cells, while “cold tumors” display lower levels of these cytotoxic immune cells (206). It is generally accepted that immunotherapies, such as immune checkpoint inhibitors, tend to be more effective in “hot tumors,” where CD8⁺ T cells play a crucial role in mounting an anti-tumor immune response (206, 207).

This section highlights how the heterogeneity of TILs and TAMs correlates with disease progression across various cancers. A recent study found that tumors with higher infiltration of CD8⁺ T cells and NK cells, combined with lower levels of M2-polarized TAMs, were significantly associated with improved progression free survival (PFS), indicated by hazard ratios (HR) less than 1, which reflects better PFS (208). For example, patients with adrenocortical carcinoma (ACC), liver hepatocellular carcinoma (LIHC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) exhibited lower M2 macrophage abundance and correspondingly better PFS (HR < 1). In contrast, cancers such as lower-grade glioma (LGG) and glioblastoma (GBM) demonstrated reduced median levels of CD8⁺ T cells and NK cells, alongside elevated M2 macrophage presence, correlating with poorer PFS (HR > 1) (208). The study also revealed notable differences within breast cancer subtypes: basal-like and HER2-enriched tumors showed significantly higher numbers of CTLs and a substantially lower likelihood of disease progression compared to luminal-A and luminal-B subtypes. Additionally, increased Treg cell infiltration was specifically associated with worse outcomes in renal clear cell carcinoma (208).

Together, these findings emphasize the complexity and heterogeneity of immune cell populations within the TME and underscore their critical influence on immunotherapy effectiveness and cancer progression. Understanding these nuances is essential for tailoring personalized treatment strategies and improving clinical outcomes.

Within a single tumor, the immune landscape can vary significantly across different regions, which greatly influences how the tumor responds to immunotherapy. Some areas may be rich in immune infiltration, characterized by the presence of activated T cells and dendritic cells, making these regions more susceptible to treatments like immune checkpoint blockade. Conversely, other parts of the TME may exhibit immunosuppressive features, marked by increased levels of myeloid-derived suppressor cells (MDSCs), Treg cells, Breg cells, and TAMs. These immunosuppressive cells dampen the activation and function of effector immune cells, leading to a diminished therapeutic response (209).

Immune-related adverse events (irAEs) are commonly observed in patients undergoing treatment with immune checkpoint inhibitors and can significantly impact patient outcomes and the overall success of immunotherapy. ICIs work by blocking inhibitory immune checkpoints, thereby enhancing T cell–mediated immune responses against tumors. However, this disruption of immune regulation can lead to a loss of immune tolerance, causing autoreactive T cells to attack healthy tissues, a process that results in irAEs resembling autoimmune diseases (210). Additionally, ICIs may increase levels of pre-existing autoantibodies, such as antithyroid antibodies, which contribute to these immune complications (211). Overproduction of inflammatory cytokines in patients receiving ICIs is also associated with systemic toxicities (212).

Among the most common irAEs are gastrointestinal issues, with symptoms generally more frequent and severe in patients treated with anti-CTLA4 therapies compared to those receiving PD1 or PDL1 inhibitors (213). Clinical trials report that ICI-associated hepatitis occurs in approximately 2% to 15% of patients (214). Inflammatory arthritis affects about 1% of patients, while arthralgia is reported in 3% to 7%. Unlike dermatologic toxicities, which often appear early, other irAEs, such as arthritis, tend to develop later, typically around two months after starting PD1/PDL1 inhibitors and about one month following initiation of anti-CTLA4 therapy (212). Understanding and managing these immune-related side effects are critical to optimizing immunotherapy safety and effectiveness.

Acquired resistance to immunotherapy often arises from disruptions in the tumor’s ability to present antigens effectively to T cells. Mutations affecting MHC molecules or components of the antigen-processing machinery can impair antigen presentation, preventing T cells from recognizing and attacking cancer cells. Such mechanisms have been documented in cancers like metastatic melanoma and prostate cancer (215).

Tumor metabolic changes also contribute to resistance. Cancer cells frequently undergo metabolic reprogramming, producing high levels of lactic acid through glycolysis. This acidifies the TME, which in turn suppresses T cell metabolism and impairs their function (215). Moreover, the tumor’s consumption of glucose can limit its availability to T cells, reducing mTOR signaling, IFNγ production, and the glycolytic capacity of T cells, further dampening their anti-tumor activity (216).

Another factor involved in acquired resistance is the increased production of adenosine by tumor cells, often driven by elevated expression of CD38. Adenosine inhibits T cell proliferation and cytotoxic functions, contributing to immune evasion (217). Genetic alterations can also play a role; for example, melanoma patients who develop resistance to PD1 blockade have been found to carry loss-of-function mutations in JAK1 or JAK2 genes. These mutations render tumor cells less responsive to the antiproliferative effects of T cell–derived IFNγ, allowing cancer cells to escape immune attack (218).

Lastly, tumor cells may undergo “antigenic drift,” where changes in tumor epitopes alter their antigenicity. This shift enables cancer cells to evade recognition by T cells, facilitating immune escape and therapy resistance (219). Together, these mechanisms highlight the complexity of acquired resistance and underscore the need for strategies that can overcome or prevent these barriers to effective immunotherapy.