Figure 1.

Mechanisms of ICB resistance from the perspective of immune response process. The success of ICB immunotherapy lies in the generation and/or reactivation of the population of CTL cells, which are also the central theme of immunotherapy. The left part of the picture depicts the normal immune response procedure which involves antigen processing and presentation, CD8⁺T cell priming, and the efficient killing of tumor cells by CTLs. Failure of immunotherapy occurs when the different phases of the cancer immunity cycle are compromised and blocked. There are numerous factors that decrease the effect of the antitumor immunity during the fight between tumor cells and immune cells. Regardless of the complexity of the immunotherapy resistance mechanisms, the consequence of these factors can be summarized as (A) failure of antigen recognition; (B) deficiency of antigen presentation; (C) poor CD8⁺ T cells infiltration and inhibited activity of CD8⁺ T cells; and (D) exhaustion of CD8⁺ T cells. Therefore, we focused on the immune response procedures, especially changes in biological function of CD8⁺T cells, with an aim to better understand the resistance mechanisms of ICB. The picture was created with BioRender.com. APC, antigen presentation cell; TAP, transporters associated with neoantigen presentation; ER, endoplasmic reticulum; MHC I, major histocompatibility complex class I; TCR, T cell receptor; CTL, cytotoxic T lymphocytes; TMB, tumor mutation burden; ITH, intra-tumor heterogeneity; DC, dendritic cell; TAM, tumor associated macrophages; CAF, cancer associated fibroblasts; TAN, tumor associated neutrophil; CTLA-4, cytotoxic T-lymphocyte antigen 4; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte activation gene‐3; PD-1, programmed cell death protein -1; TIM-3, T-cell immunoglobulin mucin-3.