Stimuli Responsive Hybrid Chitosan Nanoplatforms for Reversing Immune Exclusion in Solid Tumors: Emerging Strategies for Tumor Microenvironment Remodeling and Enhanced Cancer Immunotherapy

Abstract

Solid tumors often develop an immunosuppressive tumor microenvironment (TME) characterized by dense deposition of extracellular matrix (ECM), aberrant vasculature, stromal barriers, and suppressive immune populations. Together, these factors promote immune exclusion and diminish the efficacy of cancer immunotherapy. Recent developments in stimuli-responsive hybrid chitosan nanoplatforms have emerged as promising options to surmount these barriers for their biocompatibility, biodegradability, mucoadhesive properties, and versatile functionalization capacity. These nanoplatforms are designed to react to either internal stimuli such as pH, redox potential, enzymes, hypoxia, and reactive oxygen species or external stimuli such as light, ultrasound, and magnetic fields to allow for regulated medication release into tumor tissues. Hybrid chitosan systems with polymers, inorganic nanoparticles, and immunomodulatory agents can remodel the TME via degradation of ECM components, normalization of tumor vasculature, repolarization of tumor-associated macrophages, reduction of immunosuppressive cytokines, and enhancement of immune cell infiltration. Moreover, these systems facilitate combination therapies, which enhance antitumor immune responses by integrating chemotherapy, phototherapy, and immune checkpoint blockade. The present work discusses the new design strategies, mechanisms of action, current challenges, and potential applications of stimuli-responsive hybrid chitosan nanoplatforms to counteract immune exclusion and improve the therapeutic outcomes of cancer immunotherapy