Ludivine Bersier, L. Francisco Lorenzo‐Martín, Yi-Hsuan Chiang, Stephan Durot, Aleksander Czauderna, Tural Yarahmadov, Tania Wyss, Irena Roçi, Jaeryung Kim, Nicola Zamboni, Nicola Vannini, Caroline Pot, Tinh‐Hai Collet, Deborah Stroka, Jeremiah Bernier‐Latmani, Matthias P. Lütolf, Simone Becattini, Thibaud Koessler, Tatiana V. Petrova
Abstract 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 high CCR2 + 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.