# Enhancement of drug delivery through fibroblast activation protein–targeted near-infrared photoimmunotherapy

## TL;DR

A new therapy targeting fibroblast activation protein improves drug delivery in tumors with dense stroma.

## Contribution

FAP-targeted NIR-PIT reduces CAFs and ECM, enhancing drug penetration in desmoplastic tumors.

## Key findings

- FAP-targeted NIR-PIT selectively reduces CAFs and ECM components in 3D spheroids.
- In vivo, the therapy improves drug accumulation and antitumor efficacy when combined with chemotherapy.
- FAP expression correlates with ECM markers and microvascular collapse in esophageal cancer samples.

## 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.

Photoimmunotherapy targeting fibroblast activation protein reduces cancer-associated fibroblasts and improves drug delivery in tumors with abundant stroma and fibroblast activation