CRCs-CAFs crosstalk-targeted nano-delivery system reprograms tumor microenvironment for oxaliplatin resistance reversing and liver metastasis inhibition in colorectal cancer.

The five-year survival rate of patients with colorectal cancer (CRC) liver metastasis is less than 30 %, and chemotherapy resistance and metastatic microenvironment remodeling are the current treatment bottlenecks. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) form a "CRCs-CAFs crosstalk" with colorectal cancer cells (CRCs) by secreting dense extracellular matrix (ECM), free fatty acids (FFA), and pro-metastatic factors, driving a vicious cycle of drug resistance and metastasis. During liver metastasis, hepatic stellate cells (HSCs)-derived CAFs (HSC-CAFs) promote tumor metastasis by remodeling the pre-metastatic microenvironment. Based on clinical sample RNA sequencing and mouse single-cell sequencing to reveal ECM signal enrichment and CAFs activation characteristics, we innovatively constructed a nano-delivery system using hyaluronic acid-modified MIL-100 nanoparticles (OEMH NPs) co-loaded with oxaliplatin (OXA) and epigallocatechin gallate (EGCG). This system can target the CRCs-CAFs crosstalk through CD44 receptor: on the one hand, OEMH NPs can inhibit CAFs activation and reduce ECM deposition, improve drug penetration and down-regulate FFA metabolic reprogramming, reverse OXA resistance; on the other hand, OEMH NPs can block the transformation of HSCs to CAFs, down-regulate pro-metastatic factors such as VEGF/IL-11/ANG, induce vascular normalization, and reprogram the pre-metastatic microenvironment. This strategy can simultaneously achieve primary lesion drug sensitization and liver metastasis inhibition, providing a new paradigm for the treatment of advanced colorectal cancer to break through the traditional treatment dilemma through dual reprogramming of metabolism and microenvironment, and has significant clinical translation potential.