Abstract SY41-01: Immune checkpoint blockade induces extracellular remodeling through cytotoxic T cells expressing BMP1

Abstract The extracellular matrix (ECM) constitutes a dynamic, acellular scaffold within tumors that provides structural and biochemical cues regulating cancer cell proliferation, invasion, immune exclusion, and metastatic dissemination. While traditionally the ECM is viewed as a stromal product of fibroblasts and other mesenchymal cells, emerging evidence suggests that anti-cancer therapies themselves can profoundly reshape it. We and others have previously demonstrated that certain systemic therapies including chemotherapy induce pulmonary ECM remodeling that promotes metastatic spread. Here, we investigated whether immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, similarly affect tumor ECM composition and architecture, and how this remodeling impacts immunotherapy response. Transcriptomic analysis of breast cancer patient samples before and after ICI treatment revealed significant enrichment of ECM-associated gene signatures following therapy. In multiple murine tumor models, anti-PD-1 treatment induced pronounced ECM remodeling characterized by de novo collagen and elastin deposition, increased matrix crosslinking, and upregulation of ECM-modifying enzymes. Unexpectedly, we identified bone morphogenetic protein 1 (BMP1), a metalloprotease that activates lysyl oxidase (LOX), collagen maturation, and TGF-β signaling, as highly expressed and secreted by CD8⁺ cytotoxic T cells upon ICI stimulation. Mechanistically, CD8⁺ T cell-derived BMP1 was essential for therapy-induced ECM remodeling, and conditional inhibition of BMP1 specifically within CD8⁺ T cells reversed pathological matrix accumulation, reduced immune exclusion, and significantly enhanced anti-PD-1 efficacy across immunotherapy-resistant melanoma, breast, and lung cancer models. These findings redefine CD8⁺ T cells as active regulators of the structural tumor microenvironment rather than solely cytotoxic effectors. To therapeutically exploit this mechanism, we engineered a novel antibody-drug conjugate (ADC) platform in which a selective BMP1 enzymatic inhibitor is conjugated to an anti-PD-1 antibody backbone. This dual-mechanism construct enables checkpoint blockade while simultaneously restricting BMP1 activity within activated CD8⁺ T cells, thereby preventing therapy-induced ECM remodeling. Treatment with this ADC sensitized otherwise resistant tumors to immunotherapy and improved tumor control compared with conventional anti-PD-1 therapy. Collectively, our findings uncover a previously unrecognized immune-mediated pathway driving ECM remodeling during immunotherapy and establish selective targeting of CD8⁺ T cell-derived BMP1 as a rational strategy to overcome resistance to immunotherapy. This study provides a conceptual and translational framework for integrating tumor immunology with matrix biology to improve clinical responses in solid tumors. Citation Format: Yuval Shaked. Immune checkpoint blockade induces extracellular remodeling through cytotoxic T cells expressing BMP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY41-01.