CRISPR/Cas9-mediated genetic targeting of IRE1α or treatment with the small molecule IRE1α RNase inhibitor MKC8866 (ORIN10010), which is currently in clinical trials, significantly reprogrammed the TME; this resulted in reversal of immunosuppression, enhanced NK and CD8 + T cell infiltration, boosted interferon responses, and improved effectiveness of anti-PD-1 therapy in multiple PCa mouse models. This evidence concerns the gene PDCD1 and posterior cortical atrophy.