Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy

Abstract

Tumor hyaluronan (HA) accumulation is closely associated with the formation of a hypoxic microenvironment that is highly immunosuppressive and severely hinders the efficacy of antitumor therapeutics. To address this problem, we develop an effective HA attenuation strategy that uses an integrated nanosystem based on mesoporous polydopamine (mPDA) with excellent photothermal conversion efficiency to boost hyaluronidase (HAase) activity remotely. Upon light irradiation, the thermal effect generated by mPDA not only directly kills tumor cells that produces an in situ vaccine effect, but also significantly boosts HAase activity (∼5 folds), leading to marked HA break down. Photoheat and HA degradation synergistically reduce tumor HIF-1α expression and reverse immunosuppressive responses. Using the synergistic treatment in a breast cancer model, we find decreased infiltration of immunosuppressive cells, including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells, increased immune-activated cells, such as mature dendritic cells and CD8⁺ T cells, and reduced immune checkpoint PD-L1 expression. The resulting relief from tumor microenvironment immunosuppression significantly contributes to an enhanced antitumor effect. This study provides an effective strategy to improve the hypoxic tumor microenvironment and simultaneously promote immune-mediated tumor regression.

Keywords: Immunosuppressive tumor microenvironment; Mesoporous polydopamine; Photothermal immunotherapy; Remotely controlled hyaluronidase activity; Tumor hypoxia normalization.