Biomimetic radiosensitizers unlock radiogenetics for local interstitial radiotherapy to activate systematic immune responses and resist tumor metastasis

Abstract

Background: Similar to other local therapeutic methods, local interstitial radiotherapy (IRT) also suffers from insufficient systematic immune activation, resulting in tumor metastasis.

Results: Mn-based IRT radiosensitizers consisting of ¹³¹I, MnO₂ and bovine serum albumin (BSA) (¹³¹I-MnO₂-BSA) were engineered. Such Mn-based IRT radiosensitizers successfully unlocked radiogenetics to magnify systematic immune responses of local IRT via remodeling hypoxic and immunosuppressive microenvironments and resist tumor metastasis. The MnO₂ in ¹³¹I-MnO₂-BSA caused decomposition of H₂O₂ enriched in tumors to generate O₂ for alleviating hypoxic microenvironment and removing tumor resistances to IRT. Concurrently, hypoxia mitigation by such radiosensitizers-unlocked radiogenetics can effectively remodel immunosuppressive microenvironment associated with regulatory T (Treg) cells and tumor-associated macrophages (TAMs) infiltration inhibition to induce immunogenic cell death (ICD), which, along with hypoxia mitigation, activates systematic immune responses. More intriguingly, ¹³¹I-MnO₂-BSA-enabled radiogenetics can upregulate PD-L1 expression, which allows anti-PD-L1-combined therapy to exert a robust antitumor effect on primary tumors and elicit memory effects to suppress metastatic tumors in both tumor models (4T1 and CT26).

Conclusions: IRT radiosensitizer-unlocked radiogenetics and the corresponding design principle provide a general pathway to address the insufficient systematic immune responses of local IRT.

Keywords: Biomimetic radiosensitizers; Hypoxic and immunosuppressive microenvironment; Interstitial radiotherapy; PD-L1 upregulation; Radiogenetics.