Radiotherapy is crucial in local cancer management and needs advancements. Tumor cells elevate intracellular copper levels to promote growth and resist radiation; thus, targeted copper delivery to mitochondria could enhance radiotherapy by inducing cuproptosis in tumor cells. In this study, we engineered a multifunctional nanoliposome complex, termed Lipo-Ele@CuO2, which encapsulates both copper peroxide (CuO2) and the copper chelator elesclomol, which can delivery Cu ions to the mitochondria. The Lipo-Ele@CuO2 complex induces mitochondria-mediated cuproptosis in tumor cells and synergistically enhances the efficacy of radiotherapy. CuO2 acts as a copper donor and exhibits inherent sensitivity to acidic environments. Additionally, it depletes intracellular glutathione, thereby sensitizing cells to cuproptosis. Leveraging its pH-responsive properties in the acidic tumor microenvironment, the Lipo-Ele@CuO2 facilitate the controlled release of elesclomol, efficiently delivering copper ions to mitochondria at tumor sites. The combined in vitro and in vivo studies demonstrate that Lipo-Ele@CuO2-based therapy significantly improves antitumor efficacy and exhibits excellent safety profiles, effectively inducing cuproptosis in tumor cells and boosting the effectiveness of radiotherapy. Furthermore, metabolomic and transcriptomic analyses reveal that this combination therapy precipitates significant alterations in tumor energy metabolism, notably repressing genes related to iron-sulfur cluster assembly and glycolysis, thereby confirming the induction of cuproptosis. This therapeutic strategy provides a viable approach for addressing clinical radiotherapy resistance and demonstrates significant translational potential.

The therapeutic advantage of radiotherapy (RT) as an adjunct to first-line immunotherapy and chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC) remains unclear. This study aimed to elucidate the value of RT based on the first failure pattern of ES-SCLC. In this study, we retrospectively analyzed ES-SCLC patients treated with first-line chemotherapy and immune checkpoint inhibitors (ICIs) at Shanghai Chest Hospital from August 2018 to October 2023. Our study recorded the first failure pattern in ES-SCLC, analyzed the main sites of disease progression, explored factors that may affect prognosis and estimated the value of RT in extending patient survival in the immunotherapy era. Key endpoints included the first failure pattern, progression-free survival (PFS) and overall survival (OS). Among 344 patients, 70 (20

Radiotherapy (RT) is a critical clinical treatment for cancer. However, radioresistance often hampers its effectiveness, leading to local recurrence and therapeutic failure. Ferroptosis has been regarded as a natural barrier to tumor progression and plays a significant role in RT-mediated anticancer effects. Therefore, the simultaneous activation of ferroptosis and RT is of great significance for cancer therapy. Herein, we engineered the tumorreleasing nanozymes (BMBs), combining manganese oxide as the ferroptosis inducer and two-dimensional bismuthene with high-Z effect for augmented ferroptotic RT in a triple-enzyme-like radiosensitization manner. The nanozymes BMBs depleted glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) in the tumor microenvironment to exhibit glutathione peroxidase (GPX)-like activity and NADPH dehydrogenase (NDH)-like activity, accompanied by aberrant reactive oxygen species (ROS) production exhibiting peoxidase (POD)-like activity. In addition, the nanozymes BMBs simultaneously inactivate ferroptosis defensive system: glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) to induce ferroptosis. The strong oxidative stress induced cascade enzyodynamic effect and ferroptosis, which synergized with the twodimensional bismuthene-mediated radiosensitization to improve the efficacy of RT. Both in vitro and in vivo experiments substantiated the excellent radiotherapeutic response of the nanozymes by enhancing RT and ferroptosis. Therefore, this work demonstrates that the rational combination of nanozymes with POD/GPX/NDHlike activity and GPX4/FSP1 suppressing ability to induce ferroptosis for synergistic radiosensitization provides a viable and promising strategy for cancer treatment.

Introduction:Sentinel lymph node (SLN) is the first regional lymph node where tumor cells metastasize, and its identification and treatment are of great significance for the prevention of tumor metastasis. However, the current clinical modalities for identification and treatment of SLN are still far from satisfactory owing to their high cost, invasiveness and low accuracy. We aim to design a novel nanomedicine system for SLN imaging and treatment with high efficacy.Methods:We designed and prepared hollow mesoporous carbon spheres (HMCS) and loaded with the chemotherapeutic drug doxorubicin (DOX), which is then modified with polyvinyl pyrrolidone (PVP) to obtain nanomedicine: HMCS-PVP-DOX.Results:HMCS-PVP with a size of about 150 nm could retain in the lymph nodes for a long time and stain the lymph nodes, which could be easily observed by the naked eye. At the same time, HMCS-PVP exhibited excellent photoacoustic and photothermal imaging capabilities, realizing multimodal imaging to locate lymph nodes precisely. Due to its high specific surface area, HMCS could be largely loaded with the chemotherapeutic drug doxorubicin (DOX). HMCS-PVP-DOX displayed highly efficient synergistic chemotherapy-photothermal therapy for lymphatic metastases in both cellular and animal experiments due to its significant photothermal effect under 1064 nm laser irradiation. HMCS-PVP-DOX also displayed great stability and biosafety.Discussion:Multifunctional nanomedicine HMCS-PVP-DOX is expected to provide a novel paradigm for designing nanomedicine to the diagnosis and treatment of lymphatic metastases because of its good stability and safety.

Conventional organic photothermal conversion reagents still face some challenges for their real applications, such as the requirement of carriers for in vivo transport, uncontrolled degradation during use, reduction in photothermal conversion efficiency by repeated exposure to a near-infrared laser, and so on. Herein, uniform ZIF-8 nanoparticles were prepared first, and then carbonized and etched to form porous carbon nanoparticles (CNPs). After loading an NO donor and wrapping with red blood cell membrane, the novel CNP-NO@RBC photothermal agent integrated with in situ imaging ability was obtained. Due to the great photothermal conversion efficiency of the carbon material and the specific release of NO from the loaded NO conformer, the CNP-NO@RBCs show excellent tumour cell killing ability based on light-triggered photothermal/gas therapy at lower doses of CNP-NO@RBCs.

The local hypoxic tumor environment substantially hampers the therapeutic efficiency of radiotherapy, which typically requires the large X-ray doses for tumor treatment but induces the serious side effects. Herein, a biomimetic radiosensitized platform based on a natural in-situ oxygen-evolving photosynthetic cyanobacteria combined with two-dimensional (2D) bismuthene with high atomic-number (Z) components, is designed and engineered to effectively modulate the radiotherapy-resistant hypoxic tumor environment and achieve sufficient radiation energy deposition into tumor. Upon the exogenous sequential irradiation of 660 nm laser and X-ray beam, continuous photosynthetic oxygen evolution by the cyanobacteria and considerable generation of reactive oxygen species by the 2D bismuthene radiosensitizer substantially augmented the therapeutic efficacy of radiotherapy and suppressed the in vivo tumor growth, as demonstrated on both LLC-lung tumor xenograftbearing C57/B6 mice model and 4T1-breast tumor xenograft-bearing Balb/c mice model, further demonstrating the photosynthetic hypoxia-alleviation capability and radiosensitization performance of the engineered biomimetic radiosensitized platform. This work exemplifies a distinct paradigm on the construction of microorganism-enabled tumor-microenvironment modulation and nanoradiosensitizer-augmented radiotherapy for efficient tumor treatment.

Background: The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as “self”, evade the surveillance of the immune system, and accumulate to the tumor sites actively. Results: Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate—an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T 1 -weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. Conclusions: These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer.

ObjectiveThe advent of immune checkpoint inhibitors (ICIs) has rapidly transformed the treatment paradigm of non-small cell lung cancer (NSCLC). Despite the durability of response to ICIs, the vast majority of patients will later develop progression. However, the failure patterns of ICI treatment are unknown. Here, our study explored the failure patterns in advanced NSCLC patients treated with ICIs.MethodsA cohort of 156 IIIB or IV NSCLC patients treated with first-/second-line ICIs were retrospectively analyzed. Patients who experienced clinical benefit and then developed progression were identified. The disease progression patterns were divided into three categories: progression in new sites, progression in existing sites, and combined progression. The number of progression sites was also recorded.ResultsBefore the cutoff date, 91 (77.1%) patients had experienced disease progression; 34% of patients had progressed in the last 9 months of the first year. Fifty-three (58.2%) patients had developed progression at existing lesions, and 56 (61.5%) patients had shown ≤2 progression sites (oligo-progression). In patients with oligo-progression, the median time of disease progression was 8.23 months and the counterpart (systemic progression) was 5.97 months. The oligo-progression patients showed prolonged median overall survival (27.23 months) compared with patients with systemic progression (18.87 months).ConclusionsFailure patterns of ICI therapy were predominantly “existing” sites, and the most common lesions of progression were the lung and lymph nodes. Most patients experienced oligo-progression which occurred later than systemic progression and showed prolonged overall survival. The control of the local lesions might be beneficial to improve ICI treatment efficacy.