免疫检查点抑制（ICI）采用PD1和其配体PDL1的抗体已经促进了大量的开发互补药物的工作。虽然这其中许多是针对额外检查点蛋白的抗体，但对于针对细胞内通路，部分最近进入临床试验的小分子免疫肿瘤药物也日益引起了关注。同时，发现针对癌细胞和肿瘤微环境的致瘤性通路的小分子具有免疫刺激作用，这些药物与ICI抗体的作用相互作用，导致越来越多的联合治疗药物的批准。目前正在调查与小分子靶向癌症代谢，细胞因子/趋化因子以及先天免疫通路和T细胞检查点结合的组合。本综述讨论了在该药物开发领域中遇到的最近里程碑和障碍，以及我们对未来发展的最佳思路。© 2022. Springer Nature Limited.

The advent of immune checkpoint inhibition (ICI) using antibodies against PD1 and its ligand PDL1 has prompted substantial efforts to develop complementary drugs. Although many of these are antibodies directed against additional checkpoint proteins, there is an increasing interest in small-molecule immuno-oncology drugs that address intracellular pathways, some of which have recently entered clinical trials. In parallel, small molecules that target pro-tumorigenic pathways in cancer cells and the tumour microenvironment have been found to have immunostimulatory effects that synergize with the action of ICI antibodies, leading to the approval of an increasing number of regimens that combine such drugs. Combinations with small molecules targeting cancer metabolism, cytokine/chemokine and innate immune pathways, and T cell checkpoints are now under investigation. This Review discusses the recent milestones and hurdles encountered in this area of drug development, as well as our views on the best path forward.© 2022. Springer Nature Limited.