Prdm12 governs an epigenetic checkpoint linking neuroimmune cross-talk to CD8⁺ T cell exhaustion-suppressed antitumor immunity.

Abstract

CD8⁺ T play essential roles in antitumor immune responses. However, immunotherapy has limited clinical efficacy in many solid tumors. Here, we performed an epigenetic-wide CRISPR-Cas9 screen in CD8⁺ T cells directly under cancer immunotherapy setting and found that <i>Prdm12</i> is a transcriptional repressor implicated in nociceptive neuron development but uncharacterized within immunological contexts. <i>Prdm12</i> deletion markedly enhanced in vivo tumor clearance of mouse CD8⁺ T cells and promoted activation, effector differentiation marker expression, and cytokine secretion in both murine and human CD8⁺ T cells in vitro. Mechanistically, <i>Prdm12</i> deficiency augmented effector transcriptional programs while inhibiting exhaustion of CGRP-RAMP1 neuroimmune axis facilitation. Additionally, <i>Prdm12</i> ablation remodeled the chromatin accessibility landscape, with H3K9me3 deposition at loci regulating T cell differentiation (<i>Trib1</i> and <i>Sgk1</i>) and exhaustion (<i>Rgs1</i> and <i>Nr4a2</i>). These results together reveal a negative regulatory mechanism for CD8⁺ T cells and advance our understanding of cancer immunotherapy by linking neurobiological signaling to immune regulation.