Enzyme‐mediated remodeling of the extracellular matrix and glycocalyx to enhance immunotherapy in solid tumors

Abstract

The tumor‐associated extracellular matrix (ECM) and glycocalyx form a dynamic barrier that provides physical shielding and immunosuppressive signaling, leading to therapeutic resistance. A growing body of evidence supports enzyme‐based strategies to remodel these barriers and improve therapeutic access to tumors. This review examines enzymes that act as “path cleansers” by cleaving components of the ECM or the glycocalyx to restore the efficacy of immunotherapies. Moreover, some enzymes may exert effects beyond barrier remodeling, including modulation of signaling pathways, enhancement of immune responses, or even direct effects on the tumor. In this review, barrier‐remodeling enzymes, categorized into different classes, are discussed as potential adjuncts to cancer immunotherapy. This review also highlights the bioengineering approaches and the delivery strategies used to enhance tumor specificity, efficacy, and safety. While such therapeutic strategies show promising outcomes, the evidence hierarchy and potential translational risks are also discussed. Improved patient stratification and computationally guided enzyme discovery and protein engineering, including strategies to reduce immunogenicity, can facilitate the clinical translation of enzyme‐assisted immunotherapy.