Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell–Mediated Antitumor Immunity by Suppressing ER Stress–Associated THBS2 Signaling

Abstract The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell–mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box–binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.