Loss of SETD2-mediated H3K36me3 Drives CD8+ T Cell Exhaustion in Lung Cancer through CXCL-dependent PMN-MDSC Recruitment and Arginine Deprivation.

Immune evasion in lung cancer is tightly regulated by epigenetic mechanisms. This study identifies key epigenetic drivers of immune escape in lung cancer and elucidates how they remodel the tumor microenvironment to induce CD8+ T cell exhaustion. We performed a CRISPR-negative screen targeting 159 epigenetic regulators (mEpi driver library) in a mouse model of lung metastasis and used single-cell sequencing, cell-based experiments, and chromatin analyses to identify mechanisms of immune escape. SET domain-containing protein 2 (SETD2) emerged as a critical suppressor of immune evasion. Loss of SETD2 markedly increased lung colonization and metastasis in mice with intact T cells, whereas this effect disappeared after T cell depletion. Mechanistically, SETD2 recruited adenine-thymine-rich interaction domain-containing protein 2 (ARID2) to maintain a repressive chromatin state at genes encoding the chemokines C-X-C motif chemokine ligand 1, 2, and 5. Loss of the SETD2-ARID2 axis increased secretion of these chemokines and recruited polymorphonuclear myeloid-derived suppressor cells, which inhibit T cell responses. These cells increased expression of free fatty acid receptor 2 (FFAR2), depleted arginine from the tumor environment, and impaired signaling required for T cell activation, driving cytotoxic T cells into terminal exhaustion. Depleting polymorphonuclear myeloid-derived suppressor cells or conditionally deleting FFAR2 in these cells restored T cell function and reduced metastasis of SETD2-deficient tumors. These findings show that loss of SETD2 creates an arginine-depleted, immunosuppressive tumor environment through a chemokine-FFAR2 pathway, revealing an epigenetic-metabolic immune checkpoint that may inform combination treatments for lung cancer.