小分子IAP拮抗剂（SMAC模拟剂，SM）正在作为一种抗癌治疗进行开发。SM治疗不仅被证明可以使肿瘤细胞对TNFα介导的细胞死亡变得更加敏感，而且还具有免疫刺激性质。它们的良好安全性和耐受性，加上有前途的临床前数据，有必要进一步研究它们在肿瘤微环境中的各种效应。使用人类肿瘤细胞和成纤维细胞球体与原代免疫细胞共培养的体外模型，我们研究了SM对免疫细胞激活的影响。SM治疗会促进人类PBMC和患者来源的树突状细胞（DC）的成熟，并将肿瘤相关成纤维细胞调节为免疫相互作用型。最后，SM诱导的肿瘤坏死增强了DC激活，也导致更高的T细胞活化和浸润到肿瘤部位。这些结果突出了使用异种体外模型研究靶向治疗对肿瘤微环境不同成分的影响的相关性。©2023 The Author(s)。

Small molecule IAP antagonists - SMAC mimetics (SM) - are being developed as an anticancer therapy. SM therapy was demonstrated not only to sensitize tumor cells to TNFα-mediated cell death but also to exert immunostimulatory properties. Their good safety and tolerability profile, plus promising preclinical data, warrants further investigation into their various effects within the tumor microenvironment. Using in vitro models of human tumor cells and fibroblast spheroids co-cultured with primary immune cells, we investigated the effects of SM on immune cell activation. SM treatment induces the maturation of human PBMC- and patient-derived dendritic cells (DC), and modulates cancer-associated fibroblasts towards an immune interacting phenotype. Finally, SM-induced tumor necroptosis further enhances DC activation, leading also to higher T-cell activation and infiltration into the tumor site. These results highlight the relevance of using heterotypic in vitro models to investigate the effects of targeted therapies on different components of the tumor microenvironment.© 2023 The Author(s).