Metabolic Regulation of Anti-tumor Immunity

Immune checkpoint blockade (ICB) therapies have transformed cancer treatment over the past fifteen years, converting malignancies historically associated with dismal prognoses, such as metastatic melanoma, into more tractable diseases. However, durable clinical benefit is achieved only in a subset of patients. As of 2023, aggregate objective response rates across cancer types remained below 20%, underscoring the need to identify pathways and cellular determinants that can be leveraged to enhance anti-tumor immunity. Tumors evade immune destruction through multiple mechanisms, but two that have risen to prominence in the era of T cell–targeted ICB are: (i) cancer cell–intrinsic programs that reduce T cell recognition, including downregulation of antigen presentation machinery, and (ii) cancer cell–extrinsic mechanisms that promote dysfunction of tumor-infiltrating T cells through establishment of a nutrient-depleted, metabolically hostile tumor microenvironment (TME). To identify new therapeutic strategies to increase ICB responsiveness, we sought tractable interventions to remodel tumor metabolism and thereby enhance anti-tumor immune responses via both intrinsic and extrinsic mechanisms. First, given the central role of mitochondria in cancer metabolism and the links between mitochondrial dysfunction and inflammatory disease, we hypothesized that perturbing mitochondrial metabolism could potentiate anti-tumor immunity. We found that selective depletion of mitochondrial complex I (CI) subunit components Ndufs4 and Ndufs6 induces anti-tumor immune responses by enhancing antigen processing and presentation on MHC class I. Mechanistically, loss of these CI subunits rewires the mitochondrial tricarboxylic acid (TCA) cycle, leading to accumulation of mitochondrial acetyl-CoA that, through an as-yet undefined pathway, increases histone H3K27 acetylation at selective promoters. This epigenetic remodeling increases transcription of Nlrc5, a master regulator of antigen processing and presentation, thereby promoting cell-intrinsic upregulation of MHC class I and improved tumor cell recognition by T cells. Second, to explore strategies for engineering a more immune-permissive TME, we focused on glutathione metabolism and intratumoral redox balance. Although glutathione has long been appreciated as an important regulator of immune function, its role in cancer immunology remains incompletely defined. We demonstrate that disruption of extracellular glutathione catabolism via deletion of Gamma-glutamyl transferase 7 (Ggt7) ectoenzyme elicits a robust anti-tumor immune response. Mechanistically, increased availability of reductive equivalents promotes naïve CD8 T cell differentiation by supporting intracellular glutathione synthesis and enhances memory CD8 T cell activity through reduction of cell-surface cysteines. Together, these findings advance our understanding of how metabolic remodeling can augment anti-tumor immunity and improve responsiveness to ICB through both cancer cell– intrinsic and –extrinsic mechanisms. We anticipate that these insights will inform the development of next-generation immune-based therapies aimed at improving survival and quality of life for patients with cancer.