Overcoming Drug Resistance by Paclitaxel Resistance in Triple‐Negative Breast Cancer

Drug resistance in solid tumors has emerged as a critical challenge, with limited effective therapeutic options available. In this study, we find that chemotherapy induces an increased tumor neoantigens burden (TNB) in breast cancer patients and both non‐resistant and chemo‐resistant triple‐negative breast cancer 4T1 tumor‐bearing mice. Consistently, proteomic analysis reveals that tumor antigens derived from in vitro chemotherapy‐treated paclitaxel (PTX)‐resistant 4T1 cells (chemo‐rAg) are enriched in damage‐associated molecular patterns and neoantigens, highlighting their potential to elicit antitumor immunity against chemo‐resistant tumors. Based on these findings, we utilize the feature of PTX resistance and develop a nanovaccine incorporating chemo‐rAg and a prodrug of a toll‐like receptor 7 (TLR7) agonist. In preclinical mouse models, the nanovaccine effectively suppresses PTX‐resistant 4T1 tumor growth, and it also reverses the innate resistance of immune checkpoint inhibitors. Notably, the therapeutic benefit of the nanovaccine is augmented by chemotherapy, which facilitates in situ release of tumor antigens. These results suggest that a chemo‐rAg‐based nanovaccine represents a promising strategy based on the ′like cures like' principle to overcome drug resistance by utilizing the characteristic of the drug resistance itself. In the murine triple‐negative breast cancer (TNBC) model, chemotherapy effectively increases tumor neoantigen burden (TNB). Here, the study constructs a liposomal nanovaccine using antigens derived from in vitro chemotherapy‐treated paclitaxel‐resistant TNBC 4T1 cells. The combination of the nanovaccine and immune checkpoint inhibitor (ICI) potently suppresses the growth of subcutaneously implanted paclitaxel‐resistant 4T1 tumors, effectively overcoming the drug resistance.