Authors: Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Yong Teng
Published: 2025-04-21
DOI: 10.1158/1538-7445.am2025-2242
Source: Full article
The tricarboxylic acid (TCA) cycle, occurring within the mitochondrial matrix, plays a pivotal role in mitochondrial metabolism, which is essential for generating energy to support tumor cell proliferation and survival. CPI-613 (devimistat) is a novel systemic therapeutic that targets the TCA cycle by inhibiting pyruvate dehydrogenase (PDH) through hyperactivation of its regulatory kinases and by inducing reactive oxygen species (ROS)-mediated inhibition of ketoglutarate dehydrogenase (KGDH). Here we report a novel mechanism by which CPI-613 potentiates the antitumor response of CD8+ T cells to head and neck squamous cell carcinoma (HNSCC). Using proximity biotinylation and LC/MS analysis, we found that CPI-613 inhibits the secretion of thrombospondin-2 (THBS2), a glycoprotein linked to poor prognosis and immune evasion in HNSCC patients. Mechanistically, CPI-613 blocks the TCA cycle in HNSCC cell mitochondria, leading to endoplasmic reticulum (ER) stress and upregulation of XBP1s, which transcriptionally suppresses THBS2 expression. As a result, CPI-613-treated HNSCC cells secrete reduced levels of THBS2, which leads to the inactivation of its receptor, CD36, on CD8+ T cells. This inactivation subsequently triggers the activation of the downstream AKT/mTOR signaling pathway, enhancing the proliferation and cytotoxic potential of CD8+ T cells. These results highlight the immunomodulatory effects of CPI-613 and provide a strong rationale for developing it as a promising treatment strategy for HNSCC.