Activation of autophagy by in situ Zn2+ chelation reaction for enhanced tumor chemoimmunotherapy

Yang Yang; Yefei Zhu; Kairuo Wang; Yunqiu Miao; Yuanyuan Zhang; Jie Gao; Huanlong Qin; Yang Zhang

doi:10.1016/j.bioactmat.2023.06.022

Activation of autophagy by in situ Zn²⁺ chelation reaction for enhanced tumor chemoimmunotherapy

Bioact Mater. 2023 Jul 5:29:116-131. doi: 10.1016/j.bioactmat.2023.06.022. eCollection 2023 Nov.

Authors

Yang Yang^{1

2}, Yefei Zhu¹, Kairuo Wang¹, Yunqiu Miao¹, Yuanyuan Zhang¹, Jie Gao³, Huanlong Qin¹, Yang Zhang^{1

2}

Affiliations

¹ Nanomedicine and Intestinal Microecology Research Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, PR China.
² School of Medicine, Shanghai University, Shanghai, 200444, PR China.
³ Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai, 200433, PR China.

Abstract

Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), a process in which tumor cells convert from nonimmunogenic to immunogenic forms. However, the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment. Although autophagy is involved in activating tumor immunity, the synergistic role of autophagy in ICD remains elusive and challenging. Herein, we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion (Zn²⁺)-doped, disulfiram (DSF)-loaded mesoporous silica nanoparticles (DSF@Zn-DMSNs). Upon pH-sensitive biodegradation of DSF@Zn-DMSNs, Zn²⁺ and DSF are coreleased in the mildly acidic tumor microenvironment, leading to the formation of toxic Zn²⁺ chelate through an in situ chelation reaction. Consequently, this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns (DAMPs) but also activates autophagy, which mediates the amplified release of DAMPs to enhance ICD. In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy, thus enhancing immunotherapy by promoting the infiltration of T cells. This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.

Keywords: Autophagy; Chemoimmunotherapy; Damage-associated molecular patterns (DAMPs); Immunogenic cell death (ICD); In situ chelation.