Abstract
Antibody-drug conjugates (ADCs), exemplified by HER2-targeted Enhertu and TROP2-targeted Trodelvy, have demonstrated significant therapeutic potential in cancers. However, a subset of patients remains refractory to ADC treatment, suggesting that the efficacy requires further optimization. Here, we demonstrate that excessive cancer-associated fibroblasts (CAFs) can form a fibrotic barrier, impeding the tissue uptake of ADCs to dampen the anti-tumor efficacy. Mechanistically, cancer cells transform normal fibroblasts into FAK-activated CAFs. The proliferation of these CAFs reduces the tumor uptake of macromolecular drugs, conferring resistance to ADCs. Targeting FAK with a small molecule inhibitor IN10018 effectively diminishes the CAF-associated tumor barrier, enhancing the tumor uptake of various ADCs irrespective of their specific targets. Combination therapy with IN10018 and ADCs targeting either HER2 or TROP2 consistently yielded superior antitumor outcomes compared to monotherapies in animal models. These findings provide compelling preclinical evidence supporting the clinical evaluation of IN10018 in combination with ADCs.