Regulatory T Cells Nanoextinguisher to Manipulate Multiple Immune Evasion for Immunotherapy

Regulatory T cells (Treg) play key roles in inhibiting effective antitumor immunity. However, therapeutic Treg depletion fails to consistently enhance immune responses due to the emergence of a wave of peripherally converted Treg cells postdepletion, along with undesired off-target side effects. Here, we report a nanoextinguisher decorated with functional peptides via tumor microenvironment responsive linkers to selectively block Treg function and maintain Treg levels rather than deplete them. The nanoextinguisher specifically neutralizes TGF-beta to inhibit the recruitment of Treg cells and the conversion of naive T cells into Treg cells, thus promoting antitumor immunity. Moreover, the nanoextinguisher can alleviate tumor resistance to immunogenic photodynamic therapy, vaccination therapy, and checkpoint inhibition. The nanoextinguisher showed 30-fold potentiation in antitumor effect compared to standalone photodynamic therapy or vaccination therapy. Overall, utilizing a nanoextinguisher to inhibit Treg function without triggering reconversion represents a generalizable method to reverse immune evasion, yielding antitumor efficacy.