integrative-transcriptomic-analysis-obesity-associated-candidate

Integrative Transcriptomic Analysis of Obesity-Associated Candidate Genes in Pediatric Adipose Tissue

Tryptophan metabolism has been linked to pediatric obesity, although the transcriptomic evidence connecting obesity-associated genes with this pathway ...

Nanjing Medical University

Lung adenocarcinoma (LUAD) is one of the most common malignancies with the highest mortality globally, and it has a poor prognosis. Cell cycle checkpoints play a central role in the entire system of monitoring cell cycle processes, by regulating the signalling pathway of the cell cycle. Cell cycle checkpoints related genes (CCCRGs) have potential utility in predicting survival, and response to immunotherapies and chemotherapies. To examine this, based on CCCRGs, we identified two lung adenocarcinoma subtypes, called cluster1 and cluster2, by consensus clustering. Enrichment analysis revealed significant discrepancies between the two subtypes in gene sets associated with cell cycle activation and tumor progression. In addition, based on Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we have developed and validated a cell cycle checkpoints-related risk signature to predict prognosis, tumour immune microenvironment: (TIME), immunotherapy and chemotherapy responses for lung adenocarcinoma patients. Results from calibration plot, decision curve analysis (DCA), and time-dependent receiver operating characteristic curve (ROC) revealed that combining age, gender, pathological stages, and risk score in lung adenocarcinoma patients allowed for a more accurate and predictive nomogram. The area under curve for lung adenocarcinoma patients with 1-, 3-, 5-, and 10-year overall survival was: 0.74, 0.73, 0.75, and 0.81, respectively. Taken together, our proposed 4-CCCRG signature can serve as a clinically useful indicator to help predict patients outcomes, and could provide important guidance for immunotherapies and chemotherapies decision for lung adenocarcinoma patients.

Immune Landscape and Classification in Lung Adenocarcinoma Based on a Novel Cell Cycle Checkpoints Related Signature for Predicting Prognosis and Therapeutic Response.

Spatiotemporally-tailored activation of dendritic cells (DC) in lymph nodes (LN) remains a critical challenge for effective cancer vaccination therapy. In this study, we show that photo/sonodynamic effect can trigger the nuclear transcription factor-kappa B (NF-κB) and stimulator of interferon genes (STING) pathways activation in DC. We engineers a library of spatiotemporally-tailored STING nanoadjuvants (SNA) by conjugating the photo/sonosensitizer and STING agonist onto the biodegradable polypeptide, and co-assembling with charge-modified polypeptides. The combination of antigen-loaded SNA vaccine (SNVac) with laser irradiation or ultrasound stimulation (namely SNVac-L or SNVac-US) efficiently facilitates DC activation and induces antigen-specific CD8 T cell response in vivo comparing to the free mixture of antigen with STING agonist. We further demonstrate that SNVac-L monotherapy or combination therapy with immune checkpoint blockade (ICB) elicits antitumor immunity to reduce tumor size and prevent tumor relapse in multiple mouse tumor models. This study thus provides a potential translational strategy for spatiotemporally-tailored innate immunity stimulation of DC to potentiate cancer immunotherapy.

Engineering STING Nanoadjuvants for spatiotemporally-tailored innate immunity stimulation and cancer vaccination therapy.

Spatiotemporally-controllable regulation of innate immunity in lymph node remains a critical challenge to implement effective cancer vaccination. Here we report an ultrasound-activatable strategy to precisely stimulate innate immunity activation in vivo. Mechanistically, ultrasound-triggered mechanical and oxidative forces synchronously activate innate immune pathways in antigen-presenting cells via calcium ion influx and mitochondria DNA release. We next design a polypeptide sono-adjuvant (SONA) library with adjustable physicochemical properties for lymph node-targeting delivery. The top-performed SONA specifically activates robust and durable innate immune responses in lymph node upon localized ultrasound stimulation. The combination of SONA-based vaccine with ultrasound stimulation induces about 3.0-fold higher antigen-specific T cell responses than conventional adjuvant-based vaccines. Moreover, in syngeneic mouse models of orthotopic breast and liver tumors, the combination of SONA-based neoantigen vaccine with ultrasound stimulation markedly boosts immune checkpoint blockade therapy to suppress tumor growth and distant metastasis. Collectively, the polypeptide sono-adjuvant offers great promise for precise regulation of innate immunity and cancer vaccine therapy.

Polypeptide sono-adjuvant for ultrasound-activatable regulation of innate immunity and cancer vaccination therapy.

Conventional mRNA cancer vaccines are designed to maximize antigen potency but often overlook vaccination-induced immune resistance. In this study, we identified a negative immune regulatory mechanism, whereby mRNA vaccination induces programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) through type I interferon (IFN-I) signaling. Elevated PD-L1 expression impairs T-cell priming in lymph nodes through engagement of programmed death receptor 1 (PD-1) on T lymphocytes. To address this challenge, we developed a self-cooperative RNA vaccine (SCORV) strategy by co-delivering antigen-encoding RNA and small interfering RNA against PD-L1 (siPD-L1) within a single lipid nanoparticle (LNP). Through iterative screening of >300 ionizable lipids, we optimized a DC-targeted LNP formulation with high RNA delivery efficiency and minimal immunotoxicity. SCORV simultaneously suppresses PD-L1-mediated immune resistance during antigen presentation and enhances T cell priming while alleviating T cell exhaustion. Importantly, SCORV potentiates the tumor reactivity of adoptively transferred tumor-infiltrating lymphocytes and elicits robust antitumor immunity in murine melanoma and hepatocellular carcinoma models. This work highlights a rational design principle for mRNA vaccines that self-correct vaccination-induced immune resistance.

Article	Year
Immune Landscape and Classification in Lung Adenocarcinoma Based on a Novel Cell Cycle Checkpoints Related Signature for Predicting Prognosis and Therapeutic Response. Frontiers in genetics\| PubMed ID: 35646074	2022
Engineering STING Nanoadjuvants for spatiotemporally-tailored innate immunity stimulation and cancer vaccination therapy. Nature communications\| PubMed ID: 40595553	2025
Polypeptide sono-adjuvant for ultrasound-activatable regulation of innate immunity and cancer vaccination therapy. Nature communications\| PubMed ID: 41402324	2025
Self-Cooperative RNA Vaccine Mitigates Dendritic Cell-Mediated Acquired Immune Resistance to Potentiate Cell Therapy for Solid Tumors. Advanced materials (Deerfield Beach, Fla.)\| PubMed ID: 42427150	2026

Shiqin Li

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