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 Prdm12 is a transcriptional repressor implicated in nociceptive neuron development but uncharacterized within immunological contexts. Prdm12 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, Prdm12 deficiency augmented effector transcriptional programs while inhibiting exhaustion of CGRP-RAMP1 neuroimmune axis facilitation. Additionally, Prdm12 ablation remodeled the chromatin accessibility landscape, with H3K9me3 deposition at loci regulating T cell differentiation (Trib1 and Sgk1) and exhaustion (Rgs1 and Nr4a2). 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.