2.6 B7-H3 (CD276) and B7-H4
B7-H3 (also known as CD276) and B7-H4 (also known as B7S1, B7x, or Vtcn1)) are members of the B7 family of immune checkpoint molecules, which play crucial roles in regulating immune responses [149, 150]. These proteins are involved in maintaining immune homeostasis by delivering co-stimulatory or co-inhibitory signals to T cells and other immune cells upon interaction with their respective receptors [149, 150].
B7-H3 is a type I trans-membrane protein, discovered in 2001, that is widely expressed on both tumor cells and immune cells within the TME but but seldom in normal cells [151]. Its expression pattern varies across different cancer types but is notably upregulated in many solid tumors, including colorectal cancer, gastric cancer, esophageal cancer [152], pancreatic cancer [153], prostate cancer [154], ovarian cancer [155], and breast cancer [156].
Initially at the time of its discovery, it was reported that B7-H3 exerted a co-stimulating effect on the proliferation of both CD4+ and CD8+ T cells [157, 158, 159], but latter on a larger majority of studies has revealed that B7-H3 induces a more robust immune evasive effect when deregulated in cancers.  Suh et al. discovered that murine B7-H3 inhibits T cell proliferation when mediated by antibodies targeting the T cell receptor or allogeneic antigen-presenting cells [160]. Veenstra et al. in their study observed that B7-H3 is responsible for providing a negative costimulatory signal [161]. In osteosarcoma and hypopharyngeal squamous cell carcinoma, B7-H3 expression showed a negative correlation with the presence of circulating CD8+ tumor-infiltrating lymphocytes, suggesting its involvement in tumor immune evasion [162, 163]. A study conducted by Cong et al. found that elevated levels of CD24 and B7-H3 were associated with a poor prognosis in breast cancer patients [156]. Another study identified B7-H1 and B7-H3 as independent predictors of poor prognosis in patients with non-small cell lung cancer [164]. Additionally, a study on clear cell renal cell carcinoma patients demonstrated that higher cytoplasmic expression of B7-H3 was significantly associated with increased nucleolar grade, lymph node invasion (LNI), invasion of Gerota’s fascia, and tumor necrosis [165]. Hence, B7-H3 has garnered attention as a potential therapeutic target due to its role in promoting tumor immune evasion. In cancer, B7-H3 can exert immunosuppressive effects through multiple mechanisms. It can deliver inhibitory signals to T cells, leading to decreased T cell activation, proliferation, and cytokine production.Moreover, B7-H3 expression on tumor cells can directly promote their survival and resistance to immune-mediated destruction [166]. B7-H3 is also seen to induce drug resistance in various cancers [167, 168]. Targeting B7-H3 with specific inhibitors or blocking antibodies has shown promise in preclinical studies and early clinical trials. In vitro and in vivo studies have shown, that experimental depletion or blocking of B7-H3, enhance the anti-tumor immune response and inhibit tumor cell proliferation and migration [169, 170, 171, 172].) Attempts are being made to target B7-H3 via.,monoclonal antibodies, bispecific antibodies, antibody–drug conjugates (ADCs), CAR T cells and CAR NK cells, and B7-H3 small-molecule inhibitors [166, 172, 173]. Through these modalities, several clinical trials are in progress : targeting B7-H3 with monoclonal antibody (MGA271) [NCT01391143] [NCT02923180] [NCT02982941] [NCT02381314], targeting B7-H3 with bispecific antibodies [NCT02628535] [NCT03406949], targeting B7-H3 through ADC therapies [NCT05280470] [NCT04145622] [NCT03729596] [NCT02475213], targeting B7-H3 with CAR T cells [NCT04385173] [NCT04077866] [NCT04185038] [NCT04432649] [NCT04637503] [NCT05143151] [NCT05190185], targeting B7-H3 with CAR NK cells [NCT04630769] [NCT03056339] and radioimmunotherapy [NCT04022213] [NCT04167618] [NCT04743661] [NCT03275402]. Preliminary data from some of the clinical trials have shown promising results [174, 175].
B7-H4 is another member of the B7 family that functions as a negative regulator of T cell responses [176, 177]. It is primarily expressed on tumor cells and certain immune cells, such as macrophages and dendritic cells, within the TME [177, 178]. Similar to B7-H3, B7-H4 expression is upregulated in several cancers, including melanoma, colorectal, prostate, ovarian , breast cancer, urothelial lung and renal cell carcinoma [178, 179, 180, 181, 182]. Its expression is associated with various adverse clinicopathological features, such as larger tumor size, higher primary tumor classification, elevated TNM clinical stage, reduced tumor-infiltrating lymphocyte counts, and decreased survival rates [178, 179, 180, 181, 182]. The interaction of B7-H4 with its receptor(s) on T cells leads to inhibitory signals that dampen T cell activation and effector functions. This results in reduced T cell proliferation, cytokine secretion, and cytotoxic activity against tumor cells. B7-H4 suppresses T-cell proliferation and IL-2 production by disrupting the activation of ERK, JNK, and AKT pathways [183]. Additionally, B7-H4 can promote tumor immune evasion by modulating the function of antigen-presenting cells and enhancing the recruitment of Tregs, which suppress anti-tumor immune responses [184]. A study by Sica et al., noted that administration of B7-H4 Ig into mice impairs antigen-specific T cell responses whereas blockade of endogenous B7-H4 by specific monoclonal antibody promotes T cell responses [176]. In their study, Zhou et al. observed that B7-H4 was highly expressed in breast carcinomas. They found that B7-H4 surface expression on tumor cells was inversely correlated with CD8+ T lymphocyte infiltration, and these tumor cells exhibited enhanced growth in immunocompetent mice [177].  In human cervical cancer, a study found that B7-H4 promotes the proliferation of Tregs and the secretion of IL-10 and TGF-β1 [185]. Similarly, in colorectal cancer, Treg cell proliferation was increased along with cancer tolerance under influence of B7-H4 [182]. Various approaches, including monoclonal antibodies and fusion proteins that block the B7-H4 pathway, are being developed and evaluated in preclinical and clinical settings [186]. The development of an anti-B7-H4 monoclonal antibody for cancer treatment has been completed in preclinical studies [178].