Mitochondrial C1QBP Is Essential for T Cell Antitumor Function by Maintaining Mitochondrial Plasticity and Metabolic Fitness

The metabolic stress present in tumors microenvironment (TME) attenuates T cells anti-tumor capacity, whereas the immune function of T cells is intrinsically controlled by their mitochondrial plasticity including mitochondrial dynamics, metabolism and biogenesis. Previous studies have reported that the complement C1q binding protein (C1QBP), a mitochondrial protein, is responsible for maintenance of the mitochondrial integrity and fitness in dendritic cells and tumor cells. However, its role in T cells, especially in T cells mediated anti-tumor immunity, remains unclear. Here we show that C1QBP is required to maintain T cell anti-tumor immunity by regulating mitochondrial biogenesis, dynamics and metabolic fitness even when only one allele of C1qbp is deleted, without affecting T cells development and homeostasis. Further analysis of C1QBP in the chimeric antigen receptor (CAR) T cell therapy against B16 melanoma model confirmed the cell intrinsic role of C1QBP in regulating T cells antitumor function. Mechanistically, we found C1QBP regulated mitochondrial plasticity and metabolic fitness through mitochondrial biogenesis via the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) signaling pathway, as well as mitochondrial morphology via the phosphorylation of mitochondrial dynamics protein dynamin-related protein 1 (Drp1). In summary, our study provides a novel mitochondrial target to reprogram the immune metabolism of T cells and improve their immunotherapeutic potential against tumors.