Beyond PD‐1/PD‐L1: New Immune Checkpoints and Therapeutic Combinations in Cancer Immunotherapy

ABSTRACT Recently, immune checkpoint inhibitors (ICIs), particularly PD‐1/PD‐L1 and CTLA‐4 inhibitors, have revolutionized cancer treatment, significantly improving survival rates for various malignancies. However, ICI therapies targeting single checkpoints on T cells still face numerous challenges, such as low response rates and post‐treatment resistance. Tumor cells can evade immune surveillance within the tumor microenvironment (TME) by modulating immune checkpoints on other immune cells. Consequently, there is an urgent need to develop novel therapeutic targets for different immune cell types. Simultaneously, combining ICIs with emerging immunotherapies—such as bispecific antibodies, antibody‐drug conjugates (ADCs), CAR‐T therapies, and cancer vaccines—has emerged as a key strategy to overcome the limitations of ICI monotherapy. This review systematically summarizes recent findings on immune checkpoint targets across various immune cells and their interaction mechanisms within the TME. We explored the potential mechanisms and clinical efficacy of combining ICIs with other immunotherapies. Meanwhile, we also emphasize the importance of rationally designing combination strategies to increase clinical trial success rates. Overall, this review provides essential guidance for the development of more precise and effective cancer immunotherapy strategies.