# Efferocytosis‐Driven Polyamine Metabolism in Macrophages Enhances Cancer Stem Cell Enrichment after Chemotherapy in Ovarian Cancer

## TL;DR

This study shows how chemotherapy can lead to cancer recurrence by promoting cancer stem cells through a process involving macrophages and polyamine metabolism.

## Contribution

The study identifies a novel macrophage–polyamine–OPN axis that drives cancer stem cell enrichment after chemotherapy in ovarian cancer.

## Key findings

- Efferocytotic macrophages increase after chemotherapy and are linked to poor prognosis and cancer stem cells.
- Targeting efferocytosis reduces cancer stem cell enrichment and chemoresistance in ovarian cancer.
- ODC1-driven polyamine metabolism, particularly putrescine, promotes cancer stemness via the OPN-CD44 axis.

## Abstract

Chemotherapy‐induced enrichment of cancer stem cells (CSCs) is a key mechanism underlying acquired chemoresistance and recurrence of epithelial ovarian cancer (OC). Although chemotherapy may enrich CSCs through selection or by inducing dedifferentiation, the dynamic changes in the tumor niche and their impact on CSCs during chemotherapy remain unclear. In this study, single‐cell sequencing and multiplex immunohistochemical analysis are used to define microenvironmental changes, and a post‐chemotherapy increase in efferocytotic macrophages that phagocytosed chemotherapy‐induced apoptotic tumor cells is identified. Efferocytotic macrophages are associated with poor prognosis and CSCs in OC. Their conditioned medium facilitates OC stemness in vitro. Meanwhile, targeting efferocytosis suppresses CSC enrichment, chemoresistance, and regrowth in vivo. Mechanistically, it is demonstrated that enhanced expression of ODC1 driven by efferocytosis increases polyamine flux, particularly putrescine, by integrating metabolomics and transcriptomics. The increase in putrescine content leads to the SPP1 and OPN overexpression in macrophages, conferring cancer stemness to OC cells through the OPN‐CD44 axis. Treatment with an ODC1 selector inhibitor mitigates CSC enrichment, sensitizes tumors to cisplatin, and restricts tumor regrowth. Together, the study shows that efferocytosis and associated polyamine metabolic reprogramming support the chemotherapy‐induced enrichment of CSCs, providing new targets for addressing chemoresistance and recurrence of OC.

Chemotherapy‐induced efferocytosis drives ovarian cancer stem cell enrichment. By engulfing apoptotic cancer cells, macrophages upregulate ODC1 and produce putrescine, which elevates osteopontin (OPN) expression. Secreted OPN then activates the CD44 receptor on cancer cells, promoting stemness and chemoresistance. This study uncovers a macrophage–polyamine–OPN axis as a crucial pathway in post‐chemotherapy relapse.