Emerging phagocytosis checkpoints in cancer immunotherapy

Cancer immunotherapy, mainly including immune checkpoints-targeted therapy and the adoptive transfer of engineered immune cells, has revolutionized the oncology landscape as it utilizes patients' own immune systems in combating the cancer cells. Cancer cells escape immune surveillance by hijacking the corresponding inhibitory pathways via overexpressing checkpoint genes. Phagocytosis checkpoints, such as CD47, CD24, MHC-I, PD-L1, STC-1 and GD2, have emerged as essential checkpoints for cancer immunotherapy by functioning as don't eat me signals or interacting with eat me signals to suppress immune responses. Phagocytosis checkpoints link innate immunity and adaptive immunity in cancer immunotherapy. Genetic ablation of these phagocytosis checkpoints, as well as blockade of their signaling pathways, robustly augments phagocytosis and reduces tumor size. Among all phagocytosis checkpoints, CD47 is the most thoroughly studied and has emerged as a rising star among targets for cancer treatment. CD47-targeting antibodies and inhibitors have been investigated in various preclinical and clinical trials. However, anemia and thrombocytopenia appear to be formidable challenges since CD47 is ubiquitously expressed on erythrocytes. Here, we review the reported phagocytosis checkpoints by discussing their mechanisms and functions in cancer immunotherapy, highlight clinical progress in targeting these checkpoints and discuss challenges and potential solutions to smooth the way for combination immunotherapeutic strategies that involve both innate and adaptive immune responses.

Automated summary

Cancer immunotherapy utilizes immune checkpoints-targeted therapy and adoptive transfer of engineered immune cells to mobilize patients' own immune systems against cancer cells, revolutionizing the field of oncology. Phagocytosis checkpoints, including CD47, CD24, MHC-I, PD-L1, STC-1, and GD2, play essential roles in suppressing immune responses and linking innate and adaptive immunity in cancer immunotherapy. Genetic ablation and blockade of these checkpoints have shown promising results in enhancing phagocytosis and reducing tumor size. CD47 is the most extensively studied phagocytosis checkpoint and has emerged as a promising target for cancer treatment. However, challenges such as anemia and thrombocytopenia due to CD47's ubiquitous expression on erythrocytes need to be addressed. This review discusses the mechanisms, functions, clinical progress, challenges, and potential solutions of phagocytosis checkpoints in cancer immunotherapy, aiming to facilitate combined immunotherapeutic strategies involving both innate and adaptive immune responses.