Prostate cancer (PCa) has the second highest incidence of all malignancies in men worldwide. Advanced PCa shows overwhelming de novo resistance to immunotherapy which has revolutionized cancer treatment and achieved remarkable success across many cancer types. To combat the resistance of PCa to immunotherapy, therapeutic efforts using targeted agents to convert "cold" to "hot" tumor microenvironment (TME) are promising approaches that are currently lacking in PCa. The TME can be shaped by both cancer cell-intrinsic and extrinsic mechanisms. Because malignancies originate from genetic mutations, the mechanisms dysregulating the immune landscape in solid tumors (PCa included) can be traced back to cancer-cell-intrinsic. However, how genetic mutations affect TME and immunotherapy is poorly understood. Here, we (1) discovered chromatin effector Pygo2, as a driver of PCa and have a significant amplification in PCa patients, induced the de novo resistance to immunotherapy through suppressing cytotoxic T lymphocytes (CTLs) infiltration in the tumor area, and (2) uncovered Speckle-type POZ protein (SPOP) and chromodomain helicase DNA-binding protein 1(CHD1) which frequently mutated and deleted respectively in PCa synergistically protected prostate epithelial cells from DNA damage and implied that the PCa patients with SPOP mutation and CHD1 deletion might be susceptible to poly(ADP-ribose) polymerase inhibitors(PARPi) or DNA-damaging agents and immunotherapy because of the potential higher neoantigen expression.Although Pygo2 was identified as the driver for the amplicon 1q21.3 in PCa, it remains unclear whether Pygo2's role in PCa involves the regulation of the TME. Here, we identified a novel mechanism where Pygo2 orchestrates a p53/Sp1/Kit/Ido1 signaling network to restrict CTLs and augment regulatory T cells in prostate tumors. Importantly, genetic ablation of Pygo2 or small-molecule inhibitors (JBC117, JBC117ana) targeting the binding between Pygo2 and histone H3K4me2/3 significantly enhanced the antitumor efficacy of several modalities of immunotherapeutics, including ICB (anti-PD1/anti-CTLA4), adoptive T cell transfer, and CXCR1/2 inhibitor that blocks polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Strikingly, Pygo2-knockout and ICB combination led to a 100% cure of the RM9 murine prostate. Clinically, Pygo2 expression was inversely correlated with CTL gene signatures and CD8+ T cell infiltration in prostate cancer. Because Pygo2 is highly expressed in several other solid malignancies, therapeutic targeting of Pygo2 may have broad applications as monotherapy or immunotherapy sensitizer for the improved outcome of cancer patients. SPOP mutations are highly associated with CHD1 deletion, defining a new subtype of PCa associated with increased genomic instability. Prostate-specific single or double knockout of Spop and Chd1 mice failed to generate prostate adenocarcinoma. Compared with wild-type or single knockout mice, the double knockout prostate harbored moderately higher proliferating cells and dramatically augmented levels of γH2AX staining. SPOP mutant overexpression and CHD1 silencing synergistically sensitized BPH1 to DNA damage by camptothecin. Our results indicated that SPOP and CHD1 could synergistically promote the repair of DNA damage in prostate epithelial cells. It implied that this subtype patient might be sensitive to PARPi and immunotherapy.