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

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.