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

Abstract

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.