Abstract
The tumor microenvironment plays a key role in cancer progression and therapy resistance, with cancer-associated fibroblasts (CAFs) contributing to desmoplasia, extracellular matrix (ECM) remodeling, and elevated interstitial fluid pressure, all of which hinder drug delivery. We investigated fibroblast activation protein–targeted (FAP-targeted) near-infrared photoimmunotherapy (NIR-PIT) as a strategy to improve drug penetration in CAF-rich tumors. In clinical esophageal cancer samples, FAP expression strongly correlated with increased collagen I, hyaluronic acid, and microvascular collapse. CAF-rich 3D spheroids demonstrated elevated ECM deposition and significantly impaired drug uptake compared with CAF-poor models. FAP-targeted NIR-PIT selectively reduced CAFs, reduced ECM components, and restored drug permeability. In vivo, FAP-targeted NIR-PIT enhanced the accumulation of panitumumab and Abraxane in CAF-rich tumors and improved antitumor efficacy when combined with chemotherapy. These findings highlight FAP-targeted NIR-PIT as a promising therapeutic approach to remodel the tumor stroma and overcome drug resistance in desmoplastic solid tumors.
Authors
Seitaro Nishimura, Kazuhiro Noma, Tasuku Matsumoto, Yasushige Takeda, Tatsuya Takahashi, Hijiri Matsumoto, Kento Kawasaki, Hotaka Kawai, Tomoyoshi Kunitomo, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Shunsuke Tanabe, Toshiaki Ohara, Hiroshi Tazawa, Yasuhiro Shirakawa, Peter L. Choyke, Hisataka Kobayashi, Toshiyoshi Fujiwara
Figure 4
Impact of CAFs on drug delivery in spheroid models.
