The therapeutic effect of cancer immunotherapy is restrained by limited patient response rate caused by ‘cold’ tumors with an intrinsically immunosuppressive tumor microenvironment (TME). Activating ...stimulator of interferon genes (STING) confers promising antitumor immunity even in ‘cold’ tumors, but the further promotion of STING agonists is hindered by undesirable toxicity, low specificity and lack of controllability. Herein, an ultrasound-controllable cGAS-STING amplifying nanoagonist was constructed by coordinating mitochondria-targeting ligand triphenylphosphonium (TPP) to sonodynamic cobalt organic framework nanosheets (TPP@CoTCPP). The Co ions specifically amplify STING activation only when cytosolic mitochondrial DNA leakage is caused by sonocatalysis-induced ROS production and sensed by cGAS. A series of downstream innate immune proinflammatory responses induced by local cGAS-STING pathway activation under spatiotemporal ultrasound stimulation efficiently prime the antitumor T-cell response against bone metastatic tumor, a typical immunosuppressive tumor. We also found that the coordination of TPP augments the sonodynamic effect of CoTCPP nanosheets by reducing the band gap, improving O2 adsorption and enhancing electron transfer. Overall, our study demonstrates that the targeted and amplified cGAS-STING activation in cancer cell controlled by spatiotemporal ultrasound irradiation boosts high-efficiency sonodynamic-ionicimmunotherapy against immunosuppressive tumor.
Combined phototherapy and immunotherapy demonstrates strong potential in the treatment of metastatic cancers. An upconversion nanoparticle (UCNP) based antigen‐capturing nanoplatform is designed to ...synergize phototherapies and immunotherapy. In particular, this nanoplatform is constructed via self‐assembly of DSPE‐PEG‐maleimide and indocyanine green (ICG) onto UCNPs, followed by loading of the photosensitizer rose bengal (RB). ICG significantly enhances the RB‐based photodynamic therapy efficiency of UCNP/ICG/RB‐mal upon activation by a near‐infrared (NIR) laser, simultaneously achieving selective photothermal therapy. Most importantly, tumor‐derived protein antigens, arising from phototherapy‐treated tumor cells, can be captured and retained in situ, due to the functionality of maleimide, which further enhance the tumor antigen uptake and presentation by antigen‐presenting cells. The synergized photothermal, photodynamic, and immunological effects using light‐activated UCNP/ICG/RB‐mal induces a tumor‐specific immune response. In the experiments, intratumoral administration of UCNP/ICG/RB‐mal, followed by noninvasive irradiation with an NIR laser, destroys primary tumors and inhibits untreated distant tumors, using a poorly immunogenic, highly metastatic 4T1 mammary tumor model. With the simultaneous use of anti‐CTLA‐4, about 84% of the treated tumor‐bearing mice achieve long‐term survival and 34% of mice develop tumor‐specific immunity. Overall, this antigen‐capturing nanoplatform provides a promising approach for the treatment of metastatic cancers.
An NIR‐triggered antigen‐capturing nanoplatform is designed to synergize photodynamic, photothermal, and immunotherapy for cancer treatment. The enhanced photothermal/photodynamic effects using the nanoplatform release tumor‐derived protein antigens, which in turn are captured and retained in situ by the nanoplatform. The enhanced uptake and presentation of antigens by antigen‐presenting cells facilitate a tumor‐specific immune response to inhibit tumor metastasis.
Improving quality of life (QOL) in advanced and metastatic cancer is a priority with increasing survivorship. This systematic review synthesizes psychosocial and behavioral interventions ...incorporating culture with the goal of examining their benefit for understudied and medically underserved populations with advanced and metastatic cancer.
Reports were systematically screened for (1) a focus on advanced and metastatic cancer survivors, (2) psychosocial or behavioral intervention intended to improve QOL, (3) evidence of incorporating the culture(s) of understudied/underserved populations, and (4) availability in English. Bias was evaluated using the JBI Critical Appraisal Checklist and the Methodological index for non-randomized studies. Qualitative synthesis and quantitative meta-analyses were completed.
Eighty-six reports containing 5981 participants' data were examined. Qualitative synthesis of 23 studies identified four overarching themes relevant for incorporating culture in interventions. Meta-analysis of 19 RCTs and 4 quasi-experimental studies containing considerable heterogeneity indicated greater improvements in QOL (g = 0.84), eudaimonic well-being (g = 0.53), distress (g = -0.49), and anxiety (g = -0.37) for main intervention conditions compared to controls. Meta-analysis of 10 single-arm trials containing minimal to moderate heterogeneity found benefit for anxiety (g = -0.54), physical symptoms (g = -0.39), and depression (g = -0.38).
Psychosocial and behavioral interventions with cultural incorporation appear beneficial for improving QOL-related outcomes in advanced and metastatic cancer. Studies incorporating culture in psychosocial or behavioral interventions offer noteworthy insight and suggestions for future efforts such as attending to deep cultural structure.
Background: Cancer is the world's leading cause of death and a key hindrance to extending life expectancy. Celastrol, a bioactive compound derived from Tripterygium wilfordii, has been shown to have ...excellent antitumor activity, but its poor solubility and severe organ toxicity side effects have hampered its clinical application. Methods: In this study, a self-assembled nanodrug (PLC-NP) was designed to deliver celastrol to tumor sites while efficiently reducing its side effects by conjugating celastrol with the bioactive material LMWH and P-selectin targeting peptide (PSN). Extensive in vitro and in vivo experiments were performed to investigate both therapeutic efficacy and adverse effects. Furthermore, the specific mechanism of the antitumor activity has also been explored. Finding: The PLC-NP nanodrugs were spherical in shape, with a mean particle size of 115.83 ± 6.93 nm. PLC-NP was sufficiently stable during blood circulation, with a selective target to P-selectin-highly expressed tumor cells, followed by releasing the containing celastrol under acidic environment and high levels of esterase in tumor cells. Both in vitro and in vivo results confirmed that celastrol's antitumor and anti-metastatic abilities were not attenuated and were actually strengthened after being formed into nanodrugs. More importantly, the organ toxicities of the modified celastrol nanodrug were dramatically reduced. Mechanistic study indicated that the inactivation of PI3K/Akt/mTOR signaling pathway and ROS-mediated mitochondrial dysfunction play critical roles in celastrol-mediated autophagy and apoptosis. Interpretation: Our findings could offer a potential strategy for the translation of toxic compounds into clinical therapeutic nanomedicine. Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
Metastatic cancer is difficult to cure because of its uncontrollable nature and side effects during treatment. We constructed a reactive oxygen species (ROS)‐activated smart theranostic prodrug ...system based on an ROS active site linked with both a targeting group and an anticancer drug for efficient regional chemotherapy of metastatic cancers. The optimized prodrug (Bio‐(8)‐MB‐CPT) with biotin as the targeting group displayed high sensitivity towards ROS and selectively targeting ability towards cervical cancer cells, showing highly efficient drug release (up to 92 %) in vitro. Bio‐(8)‐MB‐CPT thus exerted strong toxicity towards cervical cancer cells, but unlike the parent drug (camptothecin), showed no toxicity towards normal cells. Moreover, the prodrug displayed significantly enhanced antitumor efficacy in vivo and eradicated the tumor with no obvious side effects (inhibition of the tumor reached up to 99.9 %).
A reactive oxygen species (ROS)‐activated smart theranostic prodrug system for efficient regional chemotherapy of metastatic cancers has been developed. The prodrug can selectively target cancer cells and be activated by highly expressed ROS, rapidly releasing drug with high efficiency. It shows significantly enhanced antitumor efficacy towards metastatic cancers (up to 99.9 %) with no obvious side effects.
Few studies have focused on palliative surgery in patients with advanced gastroesophageal junction (GEJ) or gastric cancer. We sought to evaluate clinical observational outcomes following palliative ...surgery in this population.
Patients with GEJ or gastric cancer who underwent palliative surgery (1/2010-11/2022) were identified. The primary outcomes were symptom improvement, ability to tolerate an oral diet, discharge to home, 30 "good days" without hospitalization, and receipt of systemic treatment. Postoperative outcomes and survival were secondarily evaluated.
Among 93 patients, the median age was 59 (IQR 47-68) years, and the median Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was 1 (range 0-3). The most frequent indication for palliative surgery was primary tumor obstruction 75 (81%) patients. The most common procedures were feeding tube placement in 60 (65%) and intestinal bypass in 15 (16%) patients. A total of 75 (81%) patients experienced symptom improvement. Of these, 19 (25%) developed recurrent and 49 (65%) developed new symptoms. ECOG-PS was significantly associated with symptom-free time. Among those who underwent a bypass, resection, or ostomy creation for malignant obstruction, 16 (80%) tolerated an oral diet. Postoperatively, 87 (94%) were discharged home, 72 (77%) had 30 good days, and 64 (69%) received systemic treatment. Postoperative complications occurred in 35 (38%) patients, and 7 (8%) died within 30 days. The median survival time was 7.7 (95% CI 6.4-10.40) months.
Patients with incurable GEJ or gastric cancer can benefit from palliative surgery. Prognosis and performance status should inform goals-of-care discussions and patient selection for surgical palliation.
Metastasis is the main cause of death in cancer patients. The efficacy of pharmacological therapy for cancer is limited by the heterogeneous nature of cancer cells and the lack of knowledge of ...microenvironments in metastasis. Evidence has shown that activated platelets possess both tumor-homing and metastasis-targeting properties via intrinsic cell adhesion molecules on platelets, and malaria protein VAR2CSA is able to specifically bind to oncofetal chondroitin sulfate, which is overexpressed on cancer cells with both epithelial and mesenchymal phenotypes. Inspired by these mechanisms, we developed a recombinant VAR2CSA peptide (rVAR2)-modified activated platelet-mimicking nanoparticles (rVAR2-PM/PLGA-ss-HA) by coating the surface of disulfide-containing biodegradable PLGA conjugate nanoparticles (PLGA-ss-HA) with an activated platelet membrane. The results demonstrated that the engineered 122 nm rVAR2-PM/PLGA-ss-HA inherited the innate properties of the activated platelet membrane and achieved enhanced homing to both primary and metastatic foci. The nanoparticles were endocytosed and responded to a high intracellular concentration of reduced glutathione, resulting in nanoparticle disintegration and the release of chemotherapeutic drugs to kill tumor cells. Thus, rVAR2-decorated activated platelet-targeting nanoparticles with controlled drug release provide a promising drug delivery strategy for efficient treatment of primary and metastatic cancer.
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