Fig. 3: Mechanisms of resistance to tumor immunotherapy.

T cells, pivotal in recognizing and attacking tumor cells through TCR-mediated MHC-binding peptide antigens (center), encounter resistance mechanisms originating from intrinsic (right) and extrinsic factors (left). Internal factors, primarily arising from defective antigen presentation, antigen deletion, and signaling pathway alterations due to gene mutations, collectively result in compromised T-cell recognition and response against tumor cells. External factors encompass T-cell dysfunction, up-regulation of inhibitory immune checkpoints, and the impact of the immunosuppressive Tumor Microenvironment (TME) and host factors. T-cell dysfunction and heightened inhibitory immune checkpoints contribute to immune escape by tumor cells. The immunosuppressive TME, characterized by nutrient deficiency, hypoxia, acidity, and a plethora of immunosuppressive cells, fosters an environment detrimental to antitumor immune responses. The acidic microenvironment, emanating from lactic acid release by tumor cells, inhibits the cytotoxicity and proliferation of CD8+ T cells. Moreover, lactate and chemokines (e.g., CCL5, CCL7, CXCL12) secreted by tumor cells orchestrate the recruitment and induction of immunosuppressive cells like Treg cells, tumor-associated macrophages, and myeloid-derived suppressor cells into the TME. These recruited cells further secrete inhibitory cytokines (e.g., TGF-β, IL-10, IL-35), hindering the functionality of T cells. Host factors predominantly involve patient-specific elements such as gender, age, weight, and gastrointestinal flora, all contributing to the complex landscape of tumor immunotherapy resistance.