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

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 I, MnO and bovine serum albumin (BSA) (I-MnO-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 MnO in I-MnO-BSA caused decomposition of HO enriched in tumors to generate O 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, I-MnO-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.