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<p>The contribution of chemotherapy-induced tissue injury to individual susceptibility to metastasis remains largely unexplored. We report that chemotherapy indirectly prevents colorectal cancer (CRC) liver metastases by inducing a lasting systemic “chemomemory”. Chemotherapy-induced intestinal mucositis alters nutrient availability, promoting the expansion of tryptophan-metabolizing bacteria and production of the microbial metabolite indole-3-propionic acid (IPA). IPA reprograms bone marrow myelopoiesis by redirecting common myeloid progenitor fate toward the macrophage lineage, limiting generation of immunosuppressive Ly6C<sup>high</sup>CCR2<sup>+</sup> monocytes. This shift enhances CD4<sup>+</sup> T cell antitumor function by promoting Th1 differentiation and spatially reorganizing CD8<sup>+</sup> and CD4<sup>+</sup> T cell interactions within the metastatic microenvironment. In a subset of CRC patients, circulating IPA levels increase after chemotherapy and inversely correlate with monocyte abundance, while high monocyte levels were associated with reduced survival. Our findings reveal that chemotherapy-induced intestinal injury normalizes pathological myelopoiesis through a microbiota-derived metabolite and identify IPA as a potential adjuvant to counteract monocyte-driven immunosuppression and metastasis.</p>

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Chemotherapy-driven intestinal dysbiosis and indole-3-propionic acid rewire myelopoiesis to promote a metastasis-refractory state

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Ludivine Bersier,
  • L. Francisco Lorenzo-Martin,
  • Yi-Hsuan Chiang,
  • Stephan Durot,
  • Aleksander Czauderna,
  • Tural Yarahmadov,
  • Tania Wyss Lozano,
  • Irena Roci,
  • Jaeryung Kim,
  • Nicola Zamboni,
  • Nicola Vannini,
  • Caroline Pot,
  • Tinh-Hai Collet,
  • Deborah Stroka,
  • Jeremiah Bernier-Latmani,
  • Matthias P. Lutolf,
  • Simone Becattini,
  • Thibaud Koessler,
  • Tatiana V. Petrova

摘要

The contribution of chemotherapy-induced tissue injury to individual susceptibility to metastasis remains largely unexplored. We report that chemotherapy indirectly prevents colorectal cancer (CRC) liver metastases by inducing a lasting systemic “chemomemory”. Chemotherapy-induced intestinal mucositis alters nutrient availability, promoting the expansion of tryptophan-metabolizing bacteria and production of the microbial metabolite indole-3-propionic acid (IPA). IPA reprograms bone marrow myelopoiesis by redirecting common myeloid progenitor fate toward the macrophage lineage, limiting generation of immunosuppressive Ly6ChighCCR2+ monocytes. This shift enhances CD4+ T cell antitumor function by promoting Th1 differentiation and spatially reorganizing CD8+ and CD4+ T cell interactions within the metastatic microenvironment. In a subset of CRC patients, circulating IPA levels increase after chemotherapy and inversely correlate with monocyte abundance, while high monocyte levels were associated with reduced survival. Our findings reveal that chemotherapy-induced intestinal injury normalizes pathological myelopoiesis through a microbiota-derived metabolite and identify IPA as a potential adjuvant to counteract monocyte-driven immunosuppression and metastasis.