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Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.

[This corrects the article DOI: 10.3389/fimmu.2025.1586759.].

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances the antitumor immune response. B7-H3 (CD276), a member of the B7 family that plays an immunoregulatory role in the T cell response, has been highlighted as a novel potential target for cancer immunotherapy. B7-H3 has been shown to play an inhibitory role in T cell activation and proliferation, participate in tumor immune evasion and influence both the immune response and tumor behavior through different signaling pathways. B7-H3 expression has been found to be aberrantly upregulated in many different cancer types, and an association between B7-H3 expression and poor prognosis has been established. Immunotherapy targeting B7-H3 through different approaches has been developing rapidly, and many ongoing clinical trials are exploring the safety and efficacy profiles of these therapies in cancer. In this review, we summarize the emerging research on the function and underlying pathways of B7-H3, the expression and roles of B7-H3 in different cancer types, and the advances in B7-H3-targeted therapy. Considering different tumor microenvironment characteristics and results from preclinical models to clinical practice, the research indicates that B7-H3 is a promising target for future immunotherapy, which might eventually contribute to an improvement in cancer immunotherapy that will benefit patients.

B7-H3 (CD276), a member of the B7 family of proteins, is a key player in cancer progression. This immune checkpoint molecule is selectively expressed in both tumor cells and immune cells within the tumor microenvironment. In addition to its immune checkpoint function, B7-H3 has been linked to tumor cell proliferation, metastasis, and therapeutic resistance. Furthermore, its drastic difference in protein expression levels between normal and tumor tissues suggests that targeting B7-H3 with drugs would lead to cancer-specific toxicity, minimizing harm to healthy cells. These properties make B7-H3 a promising target for cancer therapy. Recently, important advances in B7-H3 research and drug development have been reported, and these new findings, including its involvement in cellular metabolic reprograming, cancer stem cell enrichment, senescence and obesity, have expanded our knowledge and understanding of this molecule, which is important in guiding future strategies for targeting B7-H3. In this review, we briefly discuss the biology and function of B7-H3 in cancer development. We emphasize more on the latest findings and their underlying mechanisms to reflect the new advances in B7-H3 research. In addition, we discuss the new improvements of B-H3 inhibitors in cancer drug development.

The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Melanoma is the most lethal form of skin cancer, with a significantly poor prognosis after metastasis. The BRAF inhibitor dabrafenib increases response rates and overall survival (OS) in advanced‐stage melanoma; however, most patients develop resistance rapidly, highlighting the need for improved combination regimens. This study investigated the therapeutic efficacy of JI‐CJ002, an herbal extract consisting of Angelica gigas , Aconitum carmichaeli, and Zingiber officinale blended in a 2:1:3 (w/w) ratio, and assessed the combined antineoplastic effects of JI‐CJ002 with dabrafenib in melanoma. JI‐CJ002 suppressed epithelial–mesenchymal transition (EMT), invasion, and melanin synthesis, and these effects were maintained in combination with dabrafenib. The combination treatment was associated with reduced B7‐H3 expression, along with inhibition of signaling pathways implicated in melanoma progression, including JAK2/STAT3, PI3K/AKT/mTOR, and NF‐κB. Efficacy of the combination regimen was further evaluated in an A375 xenograft murine model. In vivo studies demonstrated that combination therapy reduced tumor volume without causing systemic toxicity, accompanied by decreased proliferation markers (PCNA and Ki‐67), increased apoptotic marker (cleaved caspase‐3), and decreased B7‐H3 expression in tumor tissues. These results suggest that JI‐CJ002 may enhance the antitumor activity of dabrafenib, accompanied by modulation of oncogenic pathways.

This study aimed to investigate the correlation between the expression of CD24 and B7-H3 in breast cancer tissues and the clinical significance. Expression of CD24 and B7-H3 in breast cancer and adjacent tissues were detected by immunohistochemistry. Quantitative PCR was used to detect the expression of CD24 and B7-H3 mRNA in breast cancer and adjacent tissues. The expression of CD24 and B7-H3 protein in breast cancer and adjacent tissues was detected by immunoblotting. The correlation between the expression levels of the two proteins was analyzed and the relationship between the expression of two proteins and the 5-year survival of breast cancer patients was investigated. CD24 and B7-H3 were positively expressed in breast cancer and adjacent tissues, the CD24-positive rate was 75.7 and 25.7%, respectively, and the B7-H3-positive rate was 56.8 and 43.2%, respectively, and the differences were statistically significant (P<0.05). The expression of CD24 was positively correlated with the expression of B7-H3 (Spearman's correlation coefficient r, 0.297; p=0.036). The positive and negative expression of CD24 and B7-H3 significantly affected the 5-year survival of breast cancer patients (P<0.05). Quantitative PCR results showed that the expression levels of CD24 and B7-H3 mRNA in breast cancer tissues were significantly higher than those in adjacent tissues (P<0.05). The expression levels of CD24 and B7-H3 protein in breast cancer tissues were also significantly higher than those in adjacent tissues (P<0.05). CD24 and B7-H3 were highly expressed in breast cancer, suggesting that both CD24 and B7-H3 were related to the development of breast cancer. Five-year survival analysis of breast cancer patients showed that the high expression of CD24 and B7-H3 were correlated with the poor prognosis of patients. Thus, CD24 and B7-H3 may become new targets for the treatment of breast cancer.

B7-H3 (also known as CD276) is a newly found molecule of B7 family, which may be a promising target for cancer treatment. B7-H3 protein was demonstrated to be expressed in several kinds of tumor tissues including non-small-cell lung cancer (NSCLC) and prostate cancer. Its expression is highly associated with undesirable treatment outcomes and survival time, due to function of the immune checkpoint molecule. It was classified as either a co-stimulatory molecule for T cell activation or the nonimmunological role of regulating signaling pathways. Although there is still no agreed conclusion on the function of B7-H3, it may be a valuable target for cancer therapy. This review aims to provide a comprehensive, up-to-date summary of the advances in B7-H3 targeting approaches in cancer therapy. Although several challenges remain, B7-H3 offers a new therapeutic target with increased efficacy and less toxicity in future cancer treatment.

The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of BT-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8^＋ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.

Despite advances in therapeutic strategies for colorectal cancer (CRC), CRC has a high disease incidence with significant morbidity and mortality worldwide. Notably, immunotherapy has shown limited efficacy in treating metastatic CRC, underscoring the need for alternative immunotherapeutic targets for the management of metastatic colorectal cancer (mCRC). In the present study, we evaluated the levels of the immune checkpoint proteins PD-L1, PD-L2 and B7-H3 in a large cohort retrospective study. We found that tumor B7-H3 (52.7%) was highly expressed in primary tumors compared to that in PD-L1 (33.6%) or PD-L2 (34.0%). Elevated B7-H3 expression was associated with advanced stage and the risk of distant metastasis and correlated with poor disease-free survival (DFS), suggesting that tumor B7-H3 was an independent prognostic factor associated with worse DFS in colon adenocarcinoma patients (COAD), especially high-risk COAD patients who received adjuvant chemotherapy. Furthermore, we found that B7-H3 significantly promoted cell proliferation and tumor growth in CRC. B7-H3 may stabilize EGFR to activate its downstream pathway for cancer cell proliferation and resistance to oxaliplatin (OXP). Dual targeting of B7-H3 and EGFR markedly rescued the susceptibility to chemotherapy in colorectal cancer cells and . Overall, these results showed that B7-H3 exhibited a high prevalence in COAD patients and was significantly associated with worse prognosis in COAD patients. Dual targeting of B7-H3 and EGFR signaling might be a potential therapeutic strategy for high-risk COAD patients.