Small molecule inhibitors targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for cancer immunotherapy (2020-2024).

Cancer immunotherapy, leveraging antibodies, excels in targeting efficacy but faces hurdles in tissue penetration, oral delivery, and prolonged half-life, with costly production and risk of adverse immunogenic effects. In contrast, small molecule immuno-oncology agents provide favorable pharmacokinetic properties and benign toxicity profiles. These agents are well-positioned to address the limitations of antibody-based immunotherapies, augment existing treatment modalities, and achieve synergistic effects when combined with antibodies. This review, for the first time, summarizes the recent advances (2020-2024) in small molecule inhibitors targeting PD-1/PD-L1, CTLA4, VISTA, TIM-3, and LAG3, highlighting rational design, benefits, and potential limitations. It also outlines the prospects for small-molecule immunotherapy.