Chemotherapy-driven intestinal dysbiosis and indole-3-propionic acid rewire myelopoiesis to promote a metastasis-refractory state.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41397968.
- Also identified by DOI 10.1038/s41467-025-67169-7 and PMC identifier 12827274.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<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.
Medical subject headings
- Myelopoiesis
- Dysbiosis
- Colorectal Neoplasms
- Indoles
- Liver Neoplasms
- Propionates
- Antineoplastic Agents