The article reviews the role of B7-H3 (B7 Homolog 3 Protein, CD276) in cancer immunotherapy, highlighting its significance as a novel target for improving the efficacy of current immunotherapeutic approaches. B7-H3 is a member of the B7 family of immune checkpoints, which play a crucial role in regulating immune responses. The authors discuss the pleiotropic immunomodulatory effects of B7-H3, including both co-stimulatory and co-inhibitory functions, and its association with advanced disease, poor patient survival, and resistance to checkpoint inhibitor (CI) treatments. They provide evidence that B7-H3 is aberrantly expressed in various solid malignancies, particularly in tumors less responsive to current immunotherapeutic options. The article also reviews the latest advancements in anti-B7-H3 modalities, including novel monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), CAR-T cells, and radioimmunotherapy agents, which have shown encouraging antitumor activity in preclinical models and are currently being tested in clinical trials for several cancer types. The authors emphasize the importance of understanding the intricate interactions of B7-H3 in the tumor microenvironment to enhance the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.The article reviews the role of B7-H3 (B7 Homolog 3 Protein, CD276) in cancer immunotherapy, highlighting its significance as a novel target for improving the efficacy of current immunotherapeutic approaches. B7-H3 is a member of the B7 family of immune checkpoints, which play a crucial role in regulating immune responses. The authors discuss the pleiotropic immunomodulatory effects of B7-H3, including both co-stimulatory and co-inhibitory functions, and its association with advanced disease, poor patient survival, and resistance to checkpoint inhibitor (CI) treatments. They provide evidence that B7-H3 is aberrantly expressed in various solid malignancies, particularly in tumors less responsive to current immunotherapeutic options. The article also reviews the latest advancements in anti-B7-H3 modalities, including novel monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), CAR-T cells, and radioimmunotherapy agents, which have shown encouraging antitumor activity in preclinical models and are currently being tested in clinical trials for several cancer types. The authors emphasize the importance of understanding the intricate interactions of B7-H3 in the tumor microenvironment to enhance the oncological utility of anti-B7-H3 agents and further shape their role in cancer therapeutics.