The Tumor Microenvironment Imposes Persistent ATF4 in CD8+ TILs to Obstruct Cancer Control

The T cell-intrinsic element that responds to tumor microenvironment (TME) stress to shape CD8+ tumor infiltrating lymphocyte (TIL) fate and function in solid cancers remains elusive. Here we report that the hypoxic TME imprints persistent activity of the central transcriptional node of the integrated stress response (ISR), activating transcription factor 4 (ATF4), in CD8+ TILs that results in metabolic polarity, mitochondrial oxidative stress, and cell death. Chronic ATF4 expression replicated the terminal exhaustion cell state in CD8+ T cells and high Atf4 expression in bulk tumor or peripheral T cells of patients with melanoma predicted poor response to PD-1 inhibition. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted viability among CD8+ TILs, enabling complete responses to PD-1 inhibition and conferring protection from re-emergent disease. Our multidisciplinary approach identifies chronic ATF4 activity as a barrier to immune checkpoint inhibitors, positioning ISR therapeutics as novel treatment strategies to improve efficacy of immunotherapy combinations.