A Heterojunction Structured WO_2.9-WSe₂ Nanoradiosensitizer Increases Local Tumor Ablation and Checkpoint Blockade Immunotherapy upon Low Radiation Dose

Abstract

Radiotherapy (RT) in practical use often suffers from offtarget side effects and ineffectiveness against hypoxic tumor microenvironment (TME) as well as remote metastases. With regard to these problems, herein, we provide semiconductor heterojunction structured WO 2.9 -WSe 2 -PEG nanoparticles to realize a synergistic RT/photothermal therapy (PTT)/checkpoint blockade immunotherapy (CBT) for enhanced antitumor and antimetastatic effect. Based on the heterojunction structured nanoparticle with high Z element, the nanosystem could realize non-oxygen-dependent reactive oxygen species generation by catalyzing highly expressed H 2 O 2 in TME upon X-ray irradiation, which could further induce immunogenic cell death. Meanwhile, this nanosystem could also induce hyperthermia upon near-infrared irradiation to enhance RT outcome. With the addition of anti-PD-L1 antibody-based CBT, our results give potent evidence that local RT/PTT upon mild temperature and low radiation dose could efficiently ablate local tumors and inhibit tumor metastasis as well as prevent tumor rechallenge. Our study provides not only one kind of radiosensitizer based on semiconductor nanoparticles but also a versatile nanoplatform for simultaneous triple-combined therapy (RT/PTT/CBT) for treating both local and metastasis tumors.

Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors

“…Despite the favorable results, several studies have shown limited results for complete tumor remission for ICIs with hyperthermia. Thus, triple combination strategies including ICIs with radio-/chemotherapy or TLR agonists have been studied, and they have also achieved favorable results with decreased tumor volume, increased metastatic dissemination, prevention of tumor rechallenge, and improved overall survival (115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126). A case report also found that hyperthermia and ipilimumab combined with IL-2 achieved complete clinical remission of stage IV triple-negative breast cancer with lung metastasis (127).…”

Immunogenicity of Externally Activated Nanoparticles for Cancer Therapy

“…Similarly, tungsten's high atomic number has also received interest. Dong et al [48] synthesized a WO 2.9 -WSe 2 nanoparticle system that can perform both PTT and radiosensitizer, resulting in ICD at a relatively lower temperature and dose as measured by an increase in calreticulin translocation in treated 4T1 cells in vitro. In in vivo models, combination radiotherapy and PTT mediated via these particles in addition to anti-PDL1 therapy also resulted in drastic decreases in primary tumor volume, as well as an increase in CD4+ and CD8+ T cells in the tumor microenvironment and immune memory effect, which inhibited tumor growth after a secondary inoculation (Figure 3b).…”

Combined Application of Nanotechnology and Multiple Therapies with Tumor Immune Checkpoints

“…Magnetic hyperthermia (MHT) refers to the thermal treatment technology of magnetic nanoparticles on tumors under strong alternating magnetic field (AMF) [86] . Unlike the widely used photochemotherapy, MHT can treat deep‐seated cancer cells in various organs under its decent tissue penetration [87] …”

“…[86] Unlike the widely used photochemotherapy, MHT can treat deep-seated cancer cells in various organs under its decent tissue penetration. [87] The MHT designed by Chao et al primarily based on FeNP and combines systemic anti-CTLA4 checkpoint antibodies and local immune adjuvants. They were demonstrated to be in multiple tumor models that the immune response of the vaccine system promoted by this MHT immunotherapy had powerful function of inhibiting tumor cell metastasis and prevented tumor recurrence.…”