Weimin Wang

Abstract A challenge in oncology is to rationally and effectively integrate immunotherapy with traditional modalities, including radiotherapy. Here, we demonstrate that radiotherapy induces tumor-cell ferroptosis. Ferroptosis agonists augment and ferroptosis antagonists limit radiotherapy efficacy in tumor models. Immunotherapy sensitizes tumors to radiotherapy by promoting tumor-cell ferroptosis. Mechanistically, IFNγ derived from immunotherapy-activated CD8+ T cells and radiotherapy-activated ATM independently, yet synergistically, suppresses SLC7A11, a unit of the glutamate–cystine antiporter xc−, resulting in reduced cystine uptake, enhanced tumor lipid oxidation and ferroptosis, and improved tumor control. Thus, ferroptosis is an unappreciated mechanism and focus for the development of effective combinatorial cancer therapy. Significance: This article describes ferroptosis as a previously unappreciated mechanism of action for radiotherapy. Further, it shows that ferroptosis is a novel point of synergy between immunotherapy and radiotherapy. Finally, it nominates SLC7A11, a critical regulator of ferroptosis, as a mechanistic determinant of synergy between radiotherapy and immunotherapy. This article is highlighted in the In This Issue feature, p. 1631

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with high rate of metastasis and recurrence. Although immune checkpoint blockade (ICB) has emerged as a promising type of immunotherapy in advanced HCC, treatment with ICB alone achieves an objective remission rate less than 20%. Thus, combination therapy strategies is needed to improve the treatment response rate and therapeutic effect. METHODS: A light-triggered disassembly of nanoplatform (TB/PTX@RTK) co-loaded an aggregation induced emission (AIE) photosensitizer (TB) and paclitaxel (PTX) was prepared for on-command drug release and synergistic chemo-photodynamic therapy (chemo-PDT). Nano-micelles were characterized for drug loading content, hydrodynamic size, absorption and emission spectra, reactive oxygen species production, and PTX release from micelles. The targeted fluorescence imaging of TB/PTX@RTK micelles and the synergistic anti-tumor efficacy of TB/PTX@RTK micelles-mediated chemo-PDT combined with anti-PD-L1 were assessed both in vitro and in vivo. RESULTS: The TB/PTX@RTK micelles could specifically accumulate at the tumor site through cRGD-mediated active target and facilitate image-guided PDT for tumor ablation. Once irradiated by light, the AIE photosensitizer of TB could produce ROS for PDT, and the thioketal linker could be cleaved by ROS to precise release of PTX in tumor cells. Chemo-PDT could not only synergistically inhibit tumor growth, but also induce immunogenic cell death and elicit anti-tumor immune response. Meanwhile, chemo-PDT significantly upregulated the expression of PD-L1 on tumor cell surface which could efficiently synergize with anti-PD-L1 monoclonal antibodies to induce an abscopal effect, and establish long-term immunological memory to inhibit tumor relapse and metastasis. CONCLUSION: Our results suggest that the combination of TB/PTX@RTK micelle-mediated chemo-PDT with anti-PD-L1 monoclonal antibodies can synergistically enhance systemic anti-tumor effects, and provide a novel insight into the development of new nanomedicine with precise controlled release and multimodal therapy to enhance the therapeutic efficacy of HCC.

The experimental results of a high-efficiency mid-IR laser are presented on a quasi-phase-matched single-resonated optical parametric oscillator in PPMgO:CLN pumped by a 1064 nm laser of an elliptical beam. The pump source was an acousto-optical Q-switched cw-diode-side-pumped Nd:YAG laser. The beam polarization matched the e-ee interaction in PPMgO:CLN. When the crystal was operated at 110 degrees C and the pump power was 104 W with a repetition rate of 7 kHz, average output powers of 16.7 W at 3.84 microm and 46 W at 1.47 microm were obtained. The slope efficiency of the 3.84 microm laser with respect to the pump laser was 19.1%. The M(2) factors of the 3.84 mum laser were 2.03 and 5.89 in the parallel and perpendicular directions, respectively.

Purpose: Esophageal cancer (ESCA) progression and chemoresistance are critical factors that impact the survival of patients with esophageal cancer. Cyclin dependent kinase inhibitor 3 (CDKN3) is an important regulator of the cell cycle that has received little attention, therefore the purpose of this study was to investigate CDKN3 involvement in ESCA. Methods: We first explored the public database in addition to our cohort to evaluate the expression of CDKN3 in ESCA patients. We performed bioinformative analysis on specific processes regulated by CDKN3, then we investigated the role of CDKN3 in ESCA progression and chemoresistance in vitro and in vivo. Finally, we sought to elucidate the mechanism of CDKN3 regulation of chemoresistance in ESCA. Results: We discovered that CDKN3 was highly expressed in ESCA and serves as an independent prognostic factor of this disease. Bioinformatic analysis showed CDKN3 involvement in DNA replication, the cell cycle G2/M phase transition, DNA damage repair (DDR) signaling pathways, et al Functional experiments in vitro and in vivo demonstrated that CDKN3 promoted ESCA progression and enhanced cisplatin resistance. Furthermore, CDKN3 inhibition resulted in reduced expression of RAD51, which plays a pivotal role in DDR. Overexpression of RAD51 reversed cisplatin-induced DNA damage and chemosensitivity in CDKN3 inhibited ESCA cell lines. Conclusion: The present research indicated that CDKN3 promoted ESCA progression and enhanced cisplatin resistance via RAD51, thereby influencing overall patient survival. Keywords: esophageal cancer, chemoresistance, CDKN3, RAD51, DNA damage repair