Multivalent Carbohydrate Nanocomposites for Tumor Microenvironment Remodeling to Enhance Antitumor Immunity

초록

Current cancer immunotherapeutic strategies mainly focuson remodelingthe tumor microenvironment (TME) to make it favorable for antitumorimmunity. Increasing attention has been paid to developing innovativeimmunomodulatory adjuvants that can restore weakened antitumor immunityby conferring immunogenicity to inflamed tumor tissues. Here, a galactan-enrichednanocomposite (Gal-NC) is developed from native carbohydrate structuresthrough an optimized enzymatic transformation for effective, stable,and biosafe innate immunomodulation. Gal-NC is characterized as acarbohydrate nanoadjuvant with a macrophage-targeting feature. Itis composed of repeating galactan glycopatterns derived from heteropolysaccharidestructures of plant origin. The galactan repeats of Gal-NC functionas multivalent pattern-recognition sites for Toll-like receptor 4(TLR4). Functionally, Gal-NC-mediated TLR activation induces the repolarizationof tumor-associated macrophages (TAMs) toward immunostimulatory/tumoricidalM1-like phenotypes. Gal-NC increases the intratumoral population ofcytotoxic T cells, the main effector cells of antitumor immunity,via re-educated TAMs. These TME alterations synergistically enhancethe T-cell-mediated antitumor response induced by alpha PD-1 administration,suggesting that Gal-NC has potential value as an adjuvant for immunecheckpoint blockade combination therapies. Thus, the Gal-NC modelestablished herein suggests a glycoengineering strategy to designa carbohydrate-based nanocomposite for advanced cancer immunotherapies.

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