Marelli Giulia, Morina Nicolò, Puccio Simone, Iovino Marta, Pandini Marta, Portale Federica, Carvetta Mattia, Mishra Divya, Diana Elisabetta, Meregalli Greta, Paraboschi Elvezia, Cibella Javier, Peano Clelia, Basso Gianluca, De Simone Gabriele, Camisaschi Chiara, Magrini Elena, Sartori Giulio, Karimi Elham, Colombo Piergiuseppe, Lazzeri Massimo, Casale Paolo, Morosi Lavinia, Martano Giuseppe, Asselta Rosanna, Bonavita Eduardo, Matsunami Hiro, Bertoni Francesco, Walsh Logan, Lugli Enrico, Di Mitri Diletta
Department of Biomedical Sciences, Humanitas University, Milan, Italy.
IRCCS Humanitas Research Hospital, Tumor Microenvironment Unit, Milan, Italy.
Nat Immunol. 2025 Jul;26(7):1182-1197. doi: 10.1038/s41590-025-02191-x. Epub 2025 Jun 30.
Infiltration of macrophages into tumors is a hallmark of cancer progression, and re-educating tumor-associated macrophages (TAMs) toward an antitumor status is a promising immunotherapy strategy. However, the mechanisms through which cancer cells affect macrophage education are unclear, limiting the therapeutic potential of this approach. Here we conducted an unbiased genome-wide CRISPR screen of primary macrophages. Our study confirms the function of known regulators in TAM responses and reveals new insights into the behavior of these cells. We identify olfactory and vomeronasal receptors, or chemosensors, as important drivers of a tumor-supportive macrophage phenotype across multiple cancers. In vivo deletion of selected chemosensors in TAMs resulted in cancer regression and increased infiltration of tumor-reactive CD8 T cells. In human prostate cancer tissues, palmitic acid bound to olfactory receptor 51E2 (OR51E2) expressed by TAMs, enhancing their protumor phenotype. Spatial lipidomics analysis further confirmed the presence of palmitic acid in close proximity to TAMs in prostate cancer, supporting the function of this lipid mediator in the tumor microenvironment. Overall, these data implicate chemosensors in macrophage sensing of the lipid-enriched milieu and highlight these receptors as possible therapeutic targets for enhancing antitumor immunity.
巨噬细胞浸润肿瘤是癌症进展的一个标志，将肿瘤相关巨噬细胞（TAM）重编程为抗肿瘤状态是一种有前景的免疫治疗策略。然而，癌细胞影响巨噬细胞重编程的机制尚不清楚，限制了这种方法的治疗潜力。在此，我们对原代巨噬细胞进行了无偏向全基因组CRISPR筛选。我们的研究证实了已知调节因子在TAM反应中的功能，并揭示了这些细胞行为的新见解。我们确定嗅觉和犁鼻器受体或化学传感器是多种癌症中肿瘤支持性巨噬细胞表型的重要驱动因素。在体内删除TAM中选定的化学传感器会导致癌症消退，并增加肿瘤反应性CD8 T细胞的浸润。在人类前列腺癌组织中，棕榈酸与TAM表达的嗅觉受体51E2（OR51E2）结合，增强其促肿瘤表型。空间脂质组学分析进一步证实了前列腺癌中棕榈酸在TAM附近的存在，支持这种脂质介质在肿瘤微环境中的作用。总体而言，这些数据表明化学传感器参与了巨噬细胞对富含脂质环境的感知，并突出这些受体作为增强抗肿瘤免疫力的潜在治疗靶点。
