Polysaccharide Nanocomposite Hydrogel Prevents the Polarity Reversal of β-Glucan-Activated Macrophages by Lactate Oxidase-Based Lactate Depletion for Enhanced Immunotherapy

Abstract

Modulating the immunosuppressive tumor microenvironment (TME) represents a promising strategy for improving cancer immunotherapy. A key approach involves reprogramming tumor-associated macrophages (TAMs) from a protumorigenic M2 phenotype to an antitumorigenic M1 state. However, elevated lactate concentration in the TME not only sustains the M2 phenotype but also impairs therapeutic efficacy. To address this challenge, we developed an in situ injectable carboxymethyl chitosan/oxidized sodium alginate (CMCS/OSA) hydrogel with pH-responsive release properties, coloaded with another nanosized active polysaccharide β-glucan and a lactate-depleting agent lactate oxidase (LOX). Under the acidic conditions of the TME, Schiff base bonds within the hydrogel matrix dissociate, triggering the controlled release of β-glucan nanoparticles and LOX. The β-glucan nanoparticles specifically target TAMs via the dendritic cell-associated C-type lectin 1 (Dectin 1) receptor, facilitating their phenotypic conversion from M2 to M1. Simultaneously, the released LOX continuously degrades lactate, preventing the reversion of TAMs back to the M2 phenotype. Collectively, our results demonstrated that this nanocomposite polysaccharide hydrogel system effectively promoted and maintained TAM polarization toward the M1 phenotype through the synergistic effects of immune modulation and metabolic regulation, ultimately enhancing the efficacy of tumor immunotherapy.