In situ macrophage reprogramming via micropatch engineering for safe and effective antitumor adoptive cell therapy.

Abstract

Adoptive cell therapy with macrophages holds great promise for treating solid tumors, but its clinical impact has been limited. The problem is twofold: the immunosuppressive tumor microenvironment quickly silences the anti-tumor activity of transferred cells, and systemic activation strategies often provoke off-target toxicity. Here, we describe a simple yet effective approach to overcome these barriers. We engineered primary macrophages with anti-CD11b-functionalized zinc-aluminum layered double hydroxide micropatches (LDHMP)-a surface-anchoring strategy that leaves the cells otherwise unaltered. Once the engineered cells (Mip@MΦ) reach the acidic tumor microenvironment, the micropatches degrade, releasing Zn2+ that synergizes with tumor-derived DNA to activate the STING pathway and drive repolarization toward an M1 anti-tumor phenotype. At the same time, LDHMP consumes excess H+, neutralizing the acidic milieu that normally suppresses immune function. This dual action-in situ reprogramming plus microenvironment remodeling-elicits robust, localized anti-tumor immunity without systemic toxicity. In orthotopic breast and pancreatic tumor models, Mip@MΦ treatment significantly inhibited tumor growth, reduced metastasis, and established durable immune memory. By combining a straightforward micropatch engineering strategy with insights from single-cell sequencing, our approach offers a scalable, safe, and highly effective platform for macrophage-based adoptive cell therapy.