As the Achilles heel of cancer cells, DDR deficiency is an ideal treatment target to interfere genome stability and induce tumor cell death

As the Achilles heel of cancer cells, DDR deficiency is an ideal treatment target to interfere genome stability and induce tumor cell death. significant potential improvements for the applications of checkpoint inhibitor, especially considering frequent resistance. Recent studies demonstrated that additional Ozagrel hydrochloride PARP inhibition could alleviate resistance and enhance efficacy of immune checkpoint blockade therapy via promoting cross-presentation and modifying immune microenvironment. We proposed that PARP inhibitors could enhance the PPP2R1B priming and tumor-killing activities of T cell, boost the whole cancer-immunity cycle, and thereby improve the response to immune checkpoint blockade. In this review, we focused the latest understanding of the effect of PARP inhibitors on anti-cancer immunity and PARP inhibitors combining immune checkpoint blockade therapy. Moreover, we summarized the preclinical and clinical evidence and discussed the feasibility of this combination therapy in future clinical practice. advanced or metastatic biliary tract cancer, metastatic castration-resistant prostate cancer, mucinous epithelial ovarian cancer, non-small cell lung cancer, mismatch repair, triple-negative breast cancer *Including epithelial ovarian cancer, fallopian tube cancer, primary peritoneal carcinoma, metastatic transitional cell cancer of the renal pelvis and ureter, urothelial carcinoma, high-grade serous carcinoma, endometrioid cdenocarcinoma, etc PARPi combining with anti-PD-1/PD-L1 treatment As early as 2017, Jiao et al. noticed the association between PARP inhibition and treatment-related PD-L1 upregulation [24]. In breast cancer cell lines and xenograft models, PARPi treatment significantly increased the expression of PD-L1 [24]. The results of the co-culture experiment showed that breast cancer cells undergoing Olaparib treatment were resistant to cell-killing activity of activated human peripheral blood mononuclear cells [24]. To further investigate whether additional anti-PD-L1 blockade could overcome PARPi-induced immune suppress in vivo, EMT6 syngeneic mouse models were adopted and received anti-PD-L1 blockade/Olaparib monotherapy or combination therapy [24]. Combination therapy exhibited more potent anti-cancer effect and elevated the abundance of TILs compared with monotherapies [24]. In this study, PARPi-induced PD-L1 upregulation was independent of cGAS-STING-IFN pathway [24]. Combination therapy in BRCA1/2 mutated modelsContrary to the observation of Jiao and colleagues, Ding et al. found PARPi treatment activated STING pathway and triggered robust anti-cancer immunity, as well as induced inflammation-mediated PD-L1 upregulation [118]. Researchers designed two genetically engineered mouse models bearing high-grade serous ovarian cancer: PBM (driven by p53 depletion, BRCA1 depletion, and c-Myc overexpression) and PPM (driven by p53 depletion, Ozagrel hydrochloride PTEN depletion, and c-Myc overexpression) [118]. Anti-PD-1 monotherapy showed nonsignificant effect on PBM, while concurrent Olaparib combining with anti-PD-1 treatment significantly retarded tumor growth [118]. Compared with Olaparib monotherapy, mice receiving combination therapy had prolonged survival time [118]. Further exploration in tumor immune microenvironment revealed that the abundance of TIL increased, the expression of negative co-stimulatory molecules (PD-1/Lag-3/Tim-3) decreased, and the secretion of pro-inflammation cytokines (IFN- and TNF-) elevated Ozagrel hydrochloride after Olaparib administration [118]. Besides, the expression of CD80/86 and MHC was upregulated on DCs following Olaparib treatment [118]. In the peripheral blood of mice undergoing Olaparib treatment, CD8+ T cells possessed greater capability to produce IFN- and TNF- [118]. PARPi-mediated local and systemic immune response could be abrogated by STING pathway blockade and enhanced by PD-1 inhibitor [118]. Combination therapy in BRCA1/2 proficient modelsThe investigations of combination therapy were mainly conducted in BRCA1/2 mutated tumors [119]. However, it is still Ozagrel hydrochloride controversial that patients without mutations in BRCA or other HR genes could benefit from PARPi combining ICI treatment. Ding et al. found that the combination therapy showed non-significant effect on BRCA-proficient ovarian cancers while Wang et al. found the concurrent ICI treatment remarkably enhanced the efficacy of PARPi in multiple BRCA-proficient tumors [120]. Niraparib combined with anti-PD-1/PD-L1 therapy increased the infiltration of immune cells into tumor bed and slowed the tumor growth in BRCA-proficient breast cancer, sarcoma, lung squamous cell carcinoma, and colon adenocarcinoma, as well as bladder cancer [120]. This combination strategy might conduce to broaden the application of PARPi. Regardless of BRCA status, Sen et al. interrogated the efficacy of PARPi combining with ICI treatment in small cell lung cancer (SCLC) model [110]. SCLC is a unique cancer which is characterized by TP53 and RB loss, as well as MYC amplification [121]. Dysregulated cell cycle checkpoint leads to increased replication stress [122]. In the meanwhile, the loss of RB in SCLC reduces the transcription inhibition of PARP [92]. The viability of SCLC is highly dependent on hyperactive PARP, thus SCLC is prone to be sensitive to.