There were five patients who discontinued durvalumab due to irAEs and less frequent AEs were reported in durvalumab treating group than the placebo group (Loibl et al., 2019). homeostasis as well as protecting against immune-mediated tissue damage in a variety of microenvironments. Several combination therapy strategies for the combination of PD-1/PD-L1 blockade with standard treatment modalities have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including chemotherapy, radiotherapy, targeted therapy, antiangiogenic therapy, and other immunotherapies. The corresponding clinical trials provide valuable estimates of treatment effects. Notably, several combination options significantly improve the response and efficacy of PD-1/PD-L1 blockade. This review provides a PD-1/PD-L1 clinical trial landscape survey in breast malignancy to guide the development of more effective and less toxic combination therapies. hypomethylation of the PD-1 promoter, promoting CD4+ T cell/CD8+ T cell activation, immune infiltration, and cytolytic function (Daver et al., 2018; Gonda et al., 2020; Loo Yau et al., 2021). Thus, these properties provide the basis for combining HMAs with ICBs. Androgen deprivation therapy has been observed an immunomodulatory effect in solid tumors (Drake et al., 2005; Gamat and Mcneel, 2017). Androgen was reported to be related to the productivity of antigen in different gender mice immunized with polyvinylpyrrolidone. Testosterone can be converted to several kinds of sex hormones that have immunomodulatory effects. Testosterone or androgen dihydrotestosterone (DHT) is able to improve the release of IL-10 by CD4+ T cells and suppress the immune response (Liva and Voskuhl, 2001). In addition, preclinical evidence showed that the absolute level of peripheral T cells increased under castration treatment in mice. Testosterone was also reported to increase the number of CD4+CD25+Foxp3+ Tregs. Given the theoretical basis, androgen receptor (AR) modulators have been used in combination with immunotherapy. The BRCA1/2 gene participates in DNA Mouse monoclonal to CD3.4AT3 reacts with CD3, a 20-26 kDa molecule, which is expressed on all mature T lymphocytes (approximately 60-80% of normal human peripheral blood lymphocytes), NK-T cells and some thymocytes. CD3 associated with the T-cell receptor a/b or g/d dimer also plays a role in T-cell activation and signal transduction during antigen recognition damage repair. Germline BRCA1/2 mutation has been found to be associated with deficient DNA double-strand break (DSB) damage repair capacity, which Framycetin may subsequently induces genomic instability, causes high histological grade TNBC, and younger age at first diagnosis (Copson et al., 2018). Based on this characteristic of tumor cells that carry Framycetin the BRCA mutation, poly (ADP-ribose) polymerase inhibitor (PARPi) impedes the recognition of PARP protein to bind with the single-strand break (SSB) of DNA and further hinders the repair mechanism of SSB, which finally induces synthetic lethality (Robson et al., 2017; Slade, 2020). Moreover, evidence Framycetin has supported that anti-PD-1/PD-L1 is usually Framycetin less efficacious in a noninflamed TME due to less lymphocyte infiltration and low PD-L1 expression (Zhao et al., 2019). DNA damage may lead to the activation of interferon genes (STING) simulator and NF-B signals, which in turn initiate inflammation and immune cell infiltration (Green et al., 2017; Stewart et al., 2018). In addition, BRCA mutation was reported to be correlated with the upregulation of PD-L1 (Gottlieb et al., 2017). On the other hand, PARPi function in activating IFN and recruiting effector T cells (Wang et al., 2019; Wu et al., 2021). Therefore, it is affordable to combine ICB and PARPi in tumors that carry DNA damage repair defects (Physique 2). 4 Clinical Application of PD-1/PD-L1 Blockade-Based Combination Treatment for Breast Malignancy Despite great progress in anti-PD-1/PD-L1 immunotherapy, its application to the treatment of breast cancer, especially TNBC, is a huge challenge due to the limited response rate and rapid emergence of resistance and/or serious adverse events (SAEs). Strikingly, PD-1/PD-L1 blockade combined with other treatment regimens produces a satisfactory outcome by enhancing Framycetin antitumor activity, overcoming drug resistance, and attenuating adverse reactions (Minn and Wherry, 2016). Numerous clinical trials have been initiated to assess the efficacy and safety of PD-1/PD-L1 blockades in combination with other treatment regimens. Clinical trials with results retrieved from PubMed, Medline and Clinicaltrials. gov were included and reviewed. In summary, there are a total of 28 trials involving dual-drug therapy, which contain nine chemotherapy.