Precision targeted cancer-associated fibroblast nano-regulator enhanced chemo-immunotherapy for triple-negative breast cancer.

Cancer-associated fibroblasts (CAFs), major components of the triple-negative breast cancer (TNBC) tumor microenvironment, affect tumor growth and limit the therapeutic efficacy of various clinical approaches by forming a dense stromal physical barrier, inducing chemo-resistance and promoting a tumor-immunosuppressive microenvironment. Therefore, therapeutic strategies based on targeted modulation of CAFs are promising in the treatment of TNBC. However, precise targeting of CAFs faces difficulties due to the lack of specific markers for CAFs. Here, we designed a nanoparticle co-modified with anisamide and CAF cell membrane (CAFm) to load tetrandrine as a CAF nano-regulator (TET@ACNP), which is able to precisely target and modulate CAFs. Precise targeting of CAFs was achieved by the combination of the CAFm homing effect as well as the high affinity effect between anisamide and sigma receptors overexpressed on CAFs. TET@ACNP was able to inhibit CAFs activation and reduce collagen secretion, thereby breaking the physical barrier to facilitate the penetration of the first-line chemotherapeutic agent docetaxel (DTX) and the infiltration of cytotoxic T lymphocytes. In addition, TET@ACNP alleviates chemoresistance by inhibiting the Wnt/β-catenin pathway and inhibits IGF2 expression to release the immunosuppressive microenvironment, ultimately enhancing chemotherapy effects and anti-tumor immunity. Our study proposes a comprehensive therapeutic strategy based on the precise targeting and regulation of CAFs in combination with chemotherapy to achieve multifaceted inhibition of TNBC. This is expected to be a universal platform to improve the therapeutic efficacy of different chemotherapeutic agents in various types of stroma-rich tumors.