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The five-year survival rate of patients with colorectal cancer (CRC) with liver metastasis is less than 30%. Chemotherapy resistance and the remodeling of the metastatic microenvironment are current treatment bottlenecks. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) secrete dense extracellular matrix (ECM), free fatty acids (FFA), and metastasis-promoting factors, forming a "CRCs-CAFs crosstalk" with CRC cells (CRCs), driving a vicious cycle of resistance and metastasis. During liver metastasis, CAFs derived from hepatic stellate cells (HSCs) (HSC-CAFs) promote tumor metastasis by remodeling the pre-metastatic microenvironment. Based on clinical sample RNA sequencing and mouse single-cell sequencing, the enrichment of ECM signals and activation characteristics of CAFs were revealed, and an innovative transparent hyaluronic acid-modified MIL-100 nanoparticle (OEMH NPs) and oxaliplatin (OXA) and epigallocatechin gallate (EGCG) nanodelivery system was constructed. This system can target the CRCs-CAFs crosstalk through the CD44 receptor: on the one hand, OEMH NPs can inhibit CAFs activation, reduce ECM deposition, increase drug permeability, and downregulate FFA metabolic reprogramming, reversing OXA resistance; on the other hand, OEMH NPs can block the transformation of HSCs to CAFs, downregulate VEGF/IL-11/ANG and other metastasis-promoting factors, induce vascular normalization, and reprogram the pre-metastatic microenvironment. This strategy can simultaneously achieve drug sensitization of the primary lesion and inhibition of liver metastasis, through dual reprogramming of metabolism and microenvironment, providing a new paradigm for breakthroughs in the treatment of advanced colorectal cancer and has significant clinical translational potential. This study was published in Bioactive Materials under the title "CRCs-CAFs crosstalk-targeted nano-delivery system reprograms the tumor microenvironment to reverse oxaliplatin resistance and inhibit liver metastasis in colorectal cancer".
Reference News: DOI: 10.1016/j.bioactmat.2025.08.002
