Targeting senescence-like tumor-associated macrophages sensitizes chemotherapy in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) frequently develops chemoresistance through poorly understood stromal interactions. This study aimed to elucidate the mediating role of chemotherapy-induced senescence-like tumor-associated macrophages (TAMs) in this process, including the underlying mechanisms and therapeutic potential. METHODS: Orthotopic TNBC models were employed to investigate doxorubicin (Adriamycin, ADM))-induced senescence-like phenotypes in TAMs. The senolytic agent ABT263 combined with IL-6 signaling blockade was administered in vivo to evaluate the restoration of chemosensitivity. Additionally, multiplexed immunofluorescence analysis was conducted on clinical TNBC specimens to assess the correlation between TAMs exhibiting senescence-like phenotypes and clinical outcomes. RESULTS: ADM chemotherapy induces a TAM senescence-like phenotype, marked by p16/p21 upregulation and acquisition of a senescence-associated secretory phenotype. Senescence-like TAMs exhibited pronounced IL-6 secretion, which activated the IL-6R/STAT3 axis in TNBC cells to drive the expression of drug-resistance genes and stemness markers. Depletion of senescence-like cells with the senolytic agent ABT263 or blockade of IL-6 signaling restored chemosensitivity in vivo, substantially enhancing ADM efficacy. Crucially, multiplexed immunofluorescence of clinical TNBC specimens revealed that senescence-like TAMs accumulate in chemotherapy-treated tumors and correlate with progressive disease (PD) rather than the therapeutic response (CR/PR). CONCLUSION: This study identifies chemotherapy-induced senescence-like TAMs as a key druggable driver of TNBC chemoresistance and highlights senolysis and IL-6 inhibition as strategies to overcome therapeutic resistance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13402-026-01197-3.