Fig. 1

The cancer-immunity cycle, immune-resistant mechanisms and strategies for anti-cancer immunotherapy. The anti-cancer immunity cycle (innermost circle) starts when cancer cells release tumor antigens. Antigen-presenting cells take up tumor antigens and present antigen-derived peptides to immune cells, which in turn activate the immune cells to migrate through the circulation, enter tumor sites, and kill cancer cells. The death of cancer cells induces the release of additional tumor antigens, which initiates another cancer-immunity cycle. The immune system has developed complex negative feedback loops to rein in the anti-pathogen response. These negative feedback loops have been exploited by cancer cells to evade anti-cancer immunity (middle circle). Current anti-cancer immunotherapy approaches (outermost circle) have been targeting and harnessing various mechanisms along this cancer-immunity circle. There are two major approaches for cancer immunotherapy: (1) the enhancement approach, which aims to augment “normal” anti-cancer immune mechanisms. Strategies in this category range from the traditional non-specific enhancement of IL-2 signaling to the more recent cancer-specific CAR-T cell therapy; and (2) the normalization approach, which aims to restore defective anti-cancer immunity in the tumor microenvironment. Strategies include FDA-approved immune checkpoint inhibitors and other drugs in development (e.g., inhibitors of the adenosine pathway)