Cancer cell mitochondria: the missing puzzle in predicting response to PD-1/PD-L1 inhibitors

Abstract Immunotherapy with anti-programmed cell death protein 1 (PD-1) is a promising anticancer treatment. However, only a minority of patients benefit from anti-PD-1 antibodies. Therefore, identifying the corresponding predictive factors is crucial. Emerging studies have found that the mitochondrial status of immune cells determines tumor response to anti-PD-1 antibodies. Here, we propose a novel hypothesis, based on recent experimental evidence, introducing cancer cell mitochondrial content as a new predictive factor for response to anti-PD-1 immunotherapy. A recent experiment on triple-negative breast cancer cells demonstrated that chemotherapy-induced ATPase family AAA domain–containing protein 3A (ATAD3A) expression levels regulate programmed death ligand-1 (PD-L1) on cancer cells. Accordingly, high ATAD3A expression is associated with high PD-L1 expression, poor tumor response to immunotherapy, and poor overall survival. In contrast, clinical evidence shows that high PD-L1 expression is associated with better response to immunotherapy and improved survival. This discrepancy forms the basis of our hypothesis. We propose that ATAD3A overexpression promotes poor response to anti-PD-1 therapy not by upregulating PD-L1, but by supporting mitochondrial metabolism. ATAD3A is a mitochondrial protein that maintains mitochondrial function and structure under endoplasmic reticulum stress. Therefore, mitochondrial biogenesis may serve as a novel predictive factor for response to anti-PD-(L)1 antibodies.