重编程肿瘤微环境以阻止转移：Akos 靶向实体瘤中的转移性癌症相关成纤维细胞

Background: Metastasis accounts for ~90% of cancer-related deaths and remains poorly controlled by therapies that primarily target cancer cells. Metastatic cancer-associated fibroblasts (mCAF) are key orchestrators of the tumor microenvironment, driving extracellular matrix remodeling, epithelial-mesenchymal transition, immune evasion, and metastatic dissemination. We identified in mCAF a proteoglycan-modified receptor that integrates these programs and developed Akos, a first-in-class small-molecule inhibitor that selectively blocks its formation and signaling. Here we extend those findings by defining the mechanism of action of Akos on tumor-stroma crosstalk and its molecular specificity toward a proteoglycan-modified stromal receptor in mCAF. Methods: Primary stromal cultures were established from core biopsies of patients with metastatic cancer (mCAF), non-metastatic cancer (CAF), and non-malignant tissue (BAF). Target expression and Akos modulation were evaluated by gene profiling, IHC, and western blot. Co-cultures measured mCAF-driven invasion, proliferation, and EMT with/without Akos. Prostate, breast, colorectal, and pancreatic xenografts assessed tumor growth and metastasis after Akos treatment. Systemic toxicity, PK, and stromal proteoglycan selectivity were determined. Mechanistic studies examined how Akos-modulated changes in the proteoglycan-modified receptor in mCAF translated into alterations in pro-migratory and invasive signaling in tumor cells. Results: Akos potently inhibited mCAF-induced tumor cell invasion and proliferation and reduced epithelial-mesenchymal transition markers in tumor cells. Mechanistic analyses showed that Akos selectively blocked formation of the proteoglycan-modified stromal receptor in mCAF, without affecting the expression of other stromal proteoglycans, and downregulated downstream mediators of migration, invasion, and extracellular matrix remodeling. These changes were associated with decreased activation of pro-metastatic signaling in tumor cells in co-culture. In xenograft models, Akos reduced tumor volume by up to 50-fold and tumor weight by up to 30-fold compared with vehicle and completely abrogated spontaneous metastatic foci in all evaluated models, while maintaining stable systemic exposure and no meaningful off-target toxicity. Discussion: Akos is a highly specific stromal-directed therapy that reprograms metastatic CAF by inhibiting a defined proteoglycan-dependent receptor, disrupts tumor-stroma signaling to tumor cells, and completely blocks spontaneous metastasis across multiple solid tumor models. The combination of mechanistic specificity, robust antimetastatic activity, and favorable safety profile supports the clinical development of Akos as a first-in-class antimetastatic therapy targeting the tumor microenvironment.