A supramolecular photopyroptosis nanoinducer with acidity-activatable immunomodulation for potentiating cancer immunotherapy.

Abstract

Photopyroptosis, characterized by releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs), is capable of promoting the maturation of dendritic cells (DCs) and recruitment of T lymphocytes (TLs) to activate antitumor immune responses. However, immunosuppressive regulatory T cells (Tregs) negatively influence T-cell homing and activation, leading to the immunosuppressive tumor microenvironment (ITM). Herein, a supramolecular photopyroptosis nanoplatform with an acidity-activatable immunomodulation is developed aiming to enhance cancer immunotherapy. Hydrophobic photopyroptosis inducer BF₂-chelated azadipyrromethene (Alk-BODIPY) is linked with two hydrophilic polyethylene glycol (PEG) chains, the end of which are further conjugated with immunomodulator demethylcantharidin (DMC) via an acid-fragile carboxylic amide bond. Acidic tumor microenvironment-triggered amide bond breakage realizes charge reversal, facilitating a deep tumor tissue penetration. Alk-BODIPY spatio-temporally arouses the cysteinyl aspartate specific proteinase 3 (caspase-3)/gasdermin E (GSDME)-dependent pyroptosis, and thus promotes the DCs maturation and TLs infiltration. Simultaneously, in situ DMC burst specifically inhibits serine/threonine protein phosphatase 2A (PP2A) activity of CD4⁺T cells, reducing their differentiation into Tregs. This supramolecular combination of photopyroptosis and immunoregulation hence dramatically increases the intratumoral TLs/Tregs ratio, which provides a favorable immune microenvironment to suppress tumor growth and metastasis. STATEMENT OF SIGNIFICANCE: Photopyroptosis enables to activate antitumor immune responses, yet the efficacy of which is compromised by the ITM. Herein, we develop a supramolecular photopyroptosis nanoinducer with acidity-activatable immunomodulation to potentiate tumor immunotherapy. The PP2A inhibitory effect of demethylcantharidin on CD4⁺T cells is concealed during the blood circulation, but specifically activated upon the acidity-triggered amido bond breakage, which potently suppresses Tregs differentiation. Meanwhile, photopyroptosis inducer Alk-BODIPY spatiotemporally activates the caspase-3/GSDME-dependent pyroptosis, efficiently promoting the maturation of DCs and infiltration of TLs. The boosted TLs/Tregs ratio thus reprograms the ITM and comprehensively restrains tumor growth and metastasis in vivo.