Targeting tumor–stroma crosstalk with ICAM1 antibody–drug conjugates to enable dual-compartment therapy in ovarian cancer.

e15024 Background: Antibody–drug conjugates (ADCs) have reshaped the treatment of solid tumors, yet their efficacy in ovarian cancer remains limited by stromal barriers and microenvironment-driven resistance, which are not addressed by epithelial-restricted targeting strategies. This study purposed to explore a new treatment strategy to remodel extracellular matrix of ovarian tumor in preclinical models via ICAM1 antibody drug conjugates (ADCs). Methods: The expression difference of ICAM1 was analyzed using RNAseq data from TCGA and the Genotype-Tissue Expression (GTEx) database. The prognostic analysis of ICAM1 was assessed by immunohistochemistry of tissue chip. Unbiased transcriptome-wide single-cell RNA sequencing analysis was performed using the GSE130000 dataset containing single-cell RNA expression profiling of 8 ovarian cancer samples. Two ICAM1-ADCs (ICAM1-MMAE and ICAM1-DXd) were rationally designed. The cytotoxic effect was investigated in vitro. The targeting and antitumor activity were assessed in xenograft model. The expression of ICAM1 was detected by western blot (WB) after co-cultured of ovarian cancer cells and cancer associated fibroblasts (CAFs). Sirius red staining and immunohistochemical was performed to evaluated the extracellular collagen after ICAM1-ADC treatment. Results: We identify intercellular adhesion molecule-1 (ICAM1) as a shared and dynamically regulated target across malignant epithelial cells and cancer-associated fibroblasts (CAFs), and develop ICAM1-ADCs to enable dual-compartment targeting in epithelial ovarian cancer. Integrative multi-omic and histological analyses reveal that ICAM1 is upregulated in ovarian cancer, associated with poor prognosis, enriched in CAF subsets linked to extracellular matrix remodeling, and inducible by tumor-derived soluble factors. ICAM1-ADCs conjugated to MMAE or DXd exhibit potent cytotoxicity against both ovarian cancer cells and ICAM1-positive CAFs while sparing normal ovarian epithelium. In vivo, these ADCs selectively accumulate in ovarian tumors and induce robust tumor regression. In tumor–CAF co-engrafted and intraperitoneal models, ICAM1-ADCs achieve superior tumor control accompanied by stromal remodeling marked by depletion of α-SMA⁺ fibroblasts and reduced collagen deposition. Increased ICAM1 expression in platinum-resistant clinical samples further supports its relevance in treatment-refractory disease. Conclusions: Collectively, this study establishes ICAM1 as a dual-compartment therapeutic target and provides a preclinical framework for ADCs designed to overcome stromal barriers through coordinated targeting of tumor cells and the supportive microenvironment.