The Cancer-Immunity Cycle: From Mechanism to Molecular Regulation

The cancer-immunity cycle offers a framework illustrating the cascade of anti-cancer immune responses. It conveys a feedback loop in which T cell-mediated destruction of tumor cells promotes further antigen presentation, driving further antigen presentation and T cell priming. Through this feedback mechanism, the immune system continuously adapts and refines its response as the tumor evolves ^[1].

The cancer-immunity cycle begins when tumor-derived neoantigens are released and taken up by dendritic cells (DCs), which require immunogenic signals (e.g. proinflammatory cytokines released by dying tumor cells or gut microbiota) to generate an anticancer response. DCs present these antigens to T cells, priming effector responses whose outcome depends on the balance between effector and regulatory T cells. Activated effector T cells then infiltrate the tumor, recognize and bind to cancer cells via TCR interactions. The killing of target cancer cell releases more antigens that fuel subsequent cycles. However, this cycle can be impaired at multiple steps in cancer patients, including antigen detection, T-cell priming, trafficking, tumor entry, and effector function due to suppressive factors in the tumor microenvironment ^[2].

The cancer-immunity cycle is shaped by opposing stimulators and inhibitors at each step.  Cancer antigen release is promoted by immunogenic or necrotic cell death, while tolerogenic or apoptotic death suppresses it. Antigen presentation is supported by pro-inflammatory cytokines (e.g. IL-1, IFN-α, TNF-α), CD40L/CD40, endogenous adjuvants and TLR ligands, while IL-10, IL-4, and IL-13 inhibit this step. T-cell priming and activation rely on CD28, CD137, OX40, CD27, IL-2, and IL-12, but can be blocked by CTLA-4, PD-1/PD-L1, and prostaglandins. T-cell trafficking to tumors is driven by CX3CL1, CXCL9, and CCL5, and infiltration depends on LFA-1, ICAM-1, and selectins, and these processes can be suppressed by VEGF and endothelin B receptor. Tumor recognition by T cells requires the T-cell receptor and can be reduced by decreased peptide-MHC expression. Finally, cancer cell killing is stimulated by IFN-γ and cytotoxic granules but inhibited by PD-1/PD-L1, TIM-3, M2 macrophages, Tregs, and TGF-β ^{[2] [3]}.

Together, these interconnected steps highlight the dynamic nature of antitumor immunity and reveal numerous points where tumors can subvert immune surveillance.