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<p>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<sup>+</sup> 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.</p>

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Chemosensor receptors are lipid-detecting regulators of macrophage function in cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月30日

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  • Giulia Marelli,
  • Nicolò Morina,
  • Simone Puccio,
  • Marta Iovino,
  • Marta Pandini,
  • Federica Portale,
  • Mattia Carvetta,
  • Divya Mishra,
  • Elisabetta Diana,
  • Greta Meregalli,
  • Elvezia Paraboschi,
  • Javier Cibella,
  • Clelia Peano,
  • Gianluca Basso,
  • Gabriele De Simone,
  • Chiara Camisaschi,
  • Elena Magrini,
  • Giulio Sartori,
  • Elham Karimi,
  • Piergiuseppe Colombo,
  • Massimo Lazzeri,
  • Paolo Casale,
  • Lavinia Morosi,
  • Giuseppe Martano,
  • Rosanna Asselta,
  • Eduardo Bonavita,
  • Hiro Matsunami,
  • Francesco Bertoni,
  • Logan Walsh,
  • Enrico Lugli,
  • Diletta Di Mitri

摘要

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.