Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy.

Immunotherapy, in particular immune checkpoint blockade (ICB) therapy targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, has remarkably revolutionized cancer treatment in the clinic. Anti-PD-1/PD-L1 therapy is designed to restore the antitumor response of cytotoxic T cells (CTLs) by blocking the interaction between PD-L1 on tumour cells and PD-1 on CTLs. Nevertheless, current anti-PD-1/PD-L1 therapy suffers from poor therapeutic outcomes in a large variety of solid tumours due to insufficient tumour specificity, severe cytotoxic effects, and the occurrence of immune resistance. In recent years, nanosized drug delivery systems (NDDSs), endowed with highly efficient tumour targeting and versatility for combination therapy, have paved a new avenue for cancer immunotherapy. In this review article, we summarized the recent advances in NDDSs for anti-PD-1/PD-L1 therapy. We then discussed the challenges and further provided perspectives to promote the clinical application of NDDS-based anti-PD-1/PD-L1 therapy.

Engineering Nanorobots for Tumor-Targeting Drug Delivery: From Dynamic Control to Stimuli-Responsive Strategy.

Nanotechnology has been widely applied to the fabrication of drug delivery systems in the past decades. Recently, with the progress made in microfabrication approaches, nanorobots are steadily becoming a promising means for tumor-targeting drug delivery. In general, nanorobots can be divided into two categories: nanomotors and stimuli-responsive nanorobots. Nanomotors are nanoscale systems with the ability to convert surrounding energies into mechanical motion, whereas stimuli-responsive nanorobots are featured with activatable capacity in response to various endogenous and exogenous stimulations. In this minireview, the dynamic control of nanomotors and the rational design of stimuli-responsive nanorobots are overviewed, with particular emphasis on their contribution to tumor-targeting therapy. Moreover, challenges and perspectives associated with the future development of nanorobots are presented.

From structural design to delivery: mRNA therapeutics for cancer immunotherapy.

mRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence-known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen-presenting cells (APCs) can synthesize mutant neo-antigens and multi-antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T-cell receptor (TCR), CD134, and immune-modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large-scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA-based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA-based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA-based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA-based cancer immunotherapy are also discussed.

Redox Dyshomeostasis with Dual Stimuli-Activatable Dihydroartemisinin Nanoparticles to Potentiate Ferroptotic Therapy of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to conventional therapies, including chemo-, radio-, and immunotherapy. In this study, it is first determined that a combination of dihydroartemisinin (DHA) and RSL-3 (a glutathione peroxidase 4 (GPX4) inhibitor) markedly induced ferroptosis of PDAC tumor cells. A mechanistic study revealed that DHA can react with iron ions to generate carbon radicals and deplete intracellular glutathione, thereby cumulatively triggering the lipid peroxidation of tumor cells with RSL-3-mediated GPX4 inhibition. A DHA-conjugated amphiphilic copolymer is subsequently synthesized, and intracellular acidity and oxidation dual-responsive DHA nanoparticles are further engineered for the tumor-specific co-delivery of DHA and RSL-3. The resultant nanoparticles (PDBA@RSL-3) efficiently induce ferroptosis of tumor cells in the Panc02 tumor-bearing immune-deficient mouse model, and elicit T-cell-based antitumor immunity in the immune-competent mouse model. The combination of PDBA@RSL-3 nanoparticles and programmed death ligand 1 blockade therapy efficiently inhibits PDAC tumor growth in the immune-competent mouse models. This study may provide novel insights for treatment of PDAC with ferroptosis-based immunotherapy.

Smart and versatile biomaterials for cutaneous wound healing.

The global increase of cutaneous wounds imposes huge health and financial burdens on patients and society. Despite improved wound healing outcomes, conventional wound dressings are far from ideal, owing to the complex healing process. Smart wound dressings, which are sensitive to or interact with changes in wound condition or environment, have been proposed as appealing therapeutic platforms to effectively facilitate wound healing. In this review, the wound healing processes and features of existing biomaterials are firstly introduced, followed by summarizing the mechanisms of smart responsive materials. Afterwards, recent advances and designs in smart and versatile materials of extensive applications for cutaneous wound healing were submarined. Finally, clinical progresses, challenges and future perspectives of the smart wound dressing are discussed. Overall, by mapping the composition and intrinsic structure of smart responsive materials to their individual needs of cutaneous wounds, with particular attention to the responsive mechanisms, this review is promising to advance further progress in designing smart responsive materials for wounds and drive clinical translation.

Nanovesicles loaded with a TGF-ß receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy.

The immune-excluded tumors (IETs) show limited response to current immunotherapy due to intrinsic and adaptive immune resistance. In this study, it is identified that inhibition of transforming growth factor-ß (TGF-ß) receptor 1 can relieve tumor fibrosis, thus facilitating the recruitment of tumor-infiltrating T lymphocytes. Subsequently, a nanovesicle is constructed for tumor-specific co-delivery of a TGF-ß inhibitor (LY2157299, LY) and the photosensitizer pyropheophorbide a (PPa). The LY-loaded nanovesicles suppress tumor fibrosis to promote intratumoral infiltration of T lymphocytes. Furthermore, PPa chelated with gadolinium ion is capable of fluorescence, photoacoustic and magnetic resonance triple-modal imaging-guided photodynamic therapy, to induce immunogenic death of tumor cells and elicit antitumor immunity in preclinical cancer models in female mice. These nanovesicles are further armored with a lipophilic prodrug of the bromodomain-containing protein 4 inhibitor (i.e., JQ1) to abolish programmed death ligand 1 expression of tumor cells and overcome adaptive immune resistance. This study may pave the way for nanomedicine-based immunotherapy of the IETs.

Self-Adaptive Nanoregulator to Mitigate Dynamic Immune Evasion of Pancreatic Cancer.

The advance of immunotherapy has shifted the paradigm of cancer management in clinics. Nevertheless, a considerable subset of pancreatic ductal adenocarcinoma (PDAC) patients marginally respond to current immunotherapy due to the occurrence of dynamic immune evasion arising from intrinsic and therapeutic stress. In this investigation, the pivotal role of pancreatic cancer-associated fibroblast (CAF)-induced fibrosis and tumor cell-mediated T-cell exhaustion in driving the dynamic immune evasion is identified. Building upon this discovery, the authors herein engineer a novel peptide-drug conjugate (PDC)-based self-adaptive nanoregulator for mitigating dynamic immune evasion of PDAC. The resulting nanoregulator can perform a two-stage morphology transformation from spherical micelle to nanofiber, and subsequently from nanofiber to spherical nanoparticles. Such kind of nanostructure design can facilitate differentialized delivery of CAF inhibitor in the extracellular matrix for intervening CAF-mediated tumor fibrosis, and indoleamine 2,3-dioxygenase 1 inhibitor to tumor cells for relieving IDO1-kynurenine axis-induced T-cell exhaustion. Antitumor study with the self-adaptive nanoregulator elicited persistent antitumor immunity and remarkable antitumor performance in both Panc02 and KPC tumor models in vivo. Taken together, the PDC-based self-adaptive nanoregulator may provide a novel avenue for enhanced PDAC immunotherapy.

Acid-Ionizable Iron Nanoadjuvant Augments STING Activation for Personalized Vaccination Immunotherapy of Cancer.

The critical challenge for cancer vaccine-induced T-cell immunity is the sustained activation of antigen cross-presentation in antigen-presenting cells (APCs) with innate immune stimulation. In this study, it is first discovered that the clinically used magnetic contrast agents, iron oxide nanoparticles (IONPs), markedly augment the type-I interferon (IFN-I) production profile of the stimulator of interferon genes (STING) agonist MSA-2 and achieve a 16-fold dosage-sparing effect in the human STING haplotype. Acid-ionizable copolymers are coassembled with IONPs and MSA-2 into iron nanoadjuvants to concentrate STING activation in the draining lymph nodes. The top candidate iron nanoadjuvant (PEIM) efficiently delivers the model antigen ovalbumin (OVA) to CD169+ APCs and facilitates antigen cross-presentation to elicit a 55-fold greater frequency of antigen-specific CD8+ cytotoxic T-lymphocyte response than soluble antigen. PEIM@OVA nanovaccine immunization induces potent and durable antitumor immunity to prevent tumor lung metastasis and eliminate established tumors. Moreover, PEIM nanoadjuvant is applicable to deliver autologous tumor antigen and synergizes with immune checkpoint blockade therapy for prevention of postoperative tumor recurrence and distant metastasis in B16-OVA melanoma and MC38 colorectal tumor models. The acid-ionizable iron nanoadjuvant offers a generalizable and readily translatable strategy to augment STING cascade activation and antigen cross-presentation for personalized cancer vaccination immunotherapy.

Comprehensive analyses of genomic features and mutational signatures in adenosquamous carcinoma of the lung.

Adenosquamous carcinoma (ASC) of the lung is a relatively rare tumor with strong aggressiveness and poor prognosis. The analysis of mutational signatures is becoming routine in cancer genomics and has implications for pathogenesis, classification, and prognosis. However, the distribution of mutational signatures in ASC patients has not been evaluated. In this study, we sought to reveal the landscape of genomic mutations and mutational signatures in ASC. Next-generation sequencing (NGS) technology was used to retrieve genomic information for 124 ASC patients. TP53 and EGFR were the most prevalent somatic mutations observed, and were present in 66.9% and 54.8% of patients, respectively. CDKN2A (21%), TERT (21%), and LRP1B (18.5%) mutations were also observed. An analysis of gene fusion/rearrangement characteristics revealed a total of 64 gene fusions. The highest frequency of variants was determined for ALK fusions, with six ALK-EML4 classical and two intergenic ALK fusions, followed by three CD74-ROS1 fusions and one ROS1-SYN3 fusion. EGFR 19del (45.6%), and EGFR L858R (38.2%) and its amplification (29.4%) were the top three EGFR mutations. We extracted mutational signatures from NGS data and then performed a statistical analysis in order to search for genomic and clinical features that could be linked to mutation signatures. Amongst signatures cataloged at COSMIC, the most prevalent, high-frequency base changes were for C > T; and the five most frequent signatures, from highest to lowest, were 2, 3, 1, 30, and 13. Signatures 1 and 6 were determined to be associated with age and tumor stage, respectively, and Signatures 22 and 30 were significantly related to smoking. We additionally evaluated the correlation between tumor mutational burden (TMB) and genomic variations. We found that mutations ARID2, BRCA1, and KEAP1 were associated with high TMB. The homologous recombination repair (HRR) pathway-related gene mutation displayed a slightly higher TMB than those without mutations. Our study is the first to report comprehensive genomic features and mutational signatures in Chinese ASC patients. Results obtained from our study will help the scientific community better understand signature-related mutational processes in ASC.

Toripalimab in advanced biliary tract cancer.

Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs). We explored the safety and efficacy of toripalimab plus gemcitabine and S-1 (GS) as the first-line treatment for advanced BTCs. At a one-sided significance level of 0.025, a total of 50 patients could provide 80% power to show the efficacy at targeted progression-free survival (PFS) rate at 6 months of 70% versus 40% for the combined treatment. This single-arm, phase II study enrolled 50 patients with advanced BTCs who previously received no systemic treatment. The regimen was as follows: toripalimab (240 mg, i.v., d1), gemcitabine (1,000 mg/m2, i.v., d1 and d8), and S-1 (40-60 mg bid p.o., d1-14, Q21d). The primary endpoint was progression-free survival. The secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The associations between response with PD-L1 expression, tumor mutational burden (TMB), and genetic variations were explored. Patients were enrolled from January 2019 to August 2020, with a median follow-up time of 24.0 months (IQR: 4.3-31.0 months). The 6-month PFS rate was 62%. The median PFS was 7.0 months (95% CI: 5.0-8.9 months), and median OS was 15.0 months (95% CI: 11.6-18.4 months). Forty-nine patients completed the evaluation for tumor response. The ORR was 30.6% (95% CI: 17.2%-44.0%), and the disease control rate was 87.8% (95% CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%), and immune-related colitis (2%). Among them, the grade III/IV immune-related adverse events (irAEs) were skin rash and colitis. In addition, biomarker analysis showed that negative PD-L1 expression and SMARCA4 mutation were significantly associated with worse survival outcomes, while no significant associations were observed for TP53, KRAS, or CDKN 2 A mutation as well as TMB. In conclusion, our data suggest that a regimen of toripalimab plus GS could improve PFS and OS with a good safety profile as a first-line treatment option for advanced BTC and warrants further verification.

Correlation between acute brain injury and brain metabonomics in dichlorvos-poisoned broilers.

Dichlorvos (DDVP) is an insecticide with neurotoxicity that is widely used in agricultural production and life. However, the effects of acute DDVP poisoning on brain tissue remain underinvestigated. The purpose of this study was to evaluate the differences within 15 min-6 h in plasma biochemical indexes, brain histology and metabolites among three groups of commercial broilers orally administered different dosages of DDVP one time: (1) high-dose group (11.3 mg/kg), (2) low-dose group (2.48 mg/kg) and (3) control group (0 mg/kg). The results of biochemical indexes showed that acute DDVP poisoning could cause hyperglycemia and oxidative stress in poisoned broilers. Histological examination showed that DDVP could induce brain edema, abnormal expression of glial fibrillary acidic protein (GFAP) and neuronal mitochondrial damage in broilers. Whole-brain metabolism showed that DDVP could significantly change the secretion of neurotransmitters, energy metabolism, amino acid metabolism and nucleotide metabolism. Correlation analysis showed that metabolites such as hypoxanthine, acetylcarnitine and glucose 6-phosphate were significantly correlated with blood glucose, biomarkers of oxidative stress and brain injury pathology. The results of this study provide new insights into the molecular mechanism of brain tissue responses to acute DDVP exposure in broilers and deliver important information for clinical research on neurodegenerative diseases caused by acute DDVP poisoning.