Ping Cheng

Respiratory syncytial virus (RSV) remains a major cause of severe lower respiratory tract disease in infants, older adults, and immunocompromised individuals, underscoring the need for vaccine strategies that balance systemic protection with frontline respiratory immunity. Although adenoviral and RNA-based RSV are both promising platforms, how the platform itself shapes systemic versus respiratory mucosal immunity under the same antigenic context remains insufficiently defined. We conducted a head-to-head comparison of an LNP-delivered saRNA vaccine (LNP-RSV-preF saRNA) and a recombinant Ad5-vectored vaccine (Ad5-RSV-preF) in mice using intramuscular prime-boost immunization. The two platforms drove distinct immune architectures rather than just differences in response magnitude. LNP-RSV-preF saRNA preferentially promoted respiratory mucosal immunity, including elevated BALF IgG, pulmonary antibody-secreting cells, CD69 ⁺ T cells, and lung-resident memory T (TRM) cells, as well as cycling and memory-associated CD8 ⁺ T-cell states and durable lung IgA memory. In contrast, Ad5-RSV-preF induced stronger systemic immunity, featured by higher early serum IgG, splenic polyfunctional effector T cells, enhanced germinal center/TFH responses, and effector-polarized CD8 + T cells, with sustained systemic humoral memory. Ad5-vectored and LNP-saRNA vaccine platforms induce distinct compartmentalized immune responses to the same RSV preF antigen. This study establishes a framework for rational platform selection in RSV vaccine design, enabling tailored strategies to balance systemic immunity and respiratory mucosal memory.

Oncolytic adenovirus (OAd) therapy is one of the effective treatment strategies for solid malignant tumors, and E1A is a requirement for adenovirus replication. Thus, it is very important to study how E1A regulates adenovirus replication. The p300 and E1A expression were detected by Western blot. The viral replication of OAd was detected by virus replication assay. The interaction between E1A and p300 was analyzed by immunofluorescence and immunoprecipitation assays. The therapeutic effect of OAd‐shp300 was analyzed by MTT assay and animal experiments. The results indicated that OAd infection or E1A overexpression could reduce p300 expression, implying that OAd might reduce p300 expression via E1A, and p300 knockdown could enhance viral replication and cell cytotoxicity of OAd. Furthermore, E1A promoted viral replication of OAd via mediating p300 ubiquitination degradation to inhibit the IFI16/STING/IRF3/IFN‐β signaling pathway. Additionally, OAd‐shp300 induced highly efficient viral replication and potent antitumor activity both in vitro and in vivo. In this study, OAd can reduce p300 expression by promoting its ubiquitination via E1A, thereby enhancing viral replication and cell cytotoxicity. Therefore, this study can provide a biomarker for screening patients who are sensitive to OAd and new ideas for clinical tumor treatment.

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. Methods: The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Results: Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. Conclusions: This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC.

Endoplasmic reticulum (ER) stress is a key driver of tumor progression and therapeutic resistance. However, the prognostic role of ER stress-related long non-coding RNAs (lncRNAs) in cervical cancer has not been systematically elucidated. In this study, an ER stress-related lncRNA signature was constructed to evaluate patient prognosis and therapeutic responsiveness. Transcriptomic datasets derived from The Cancer Genome Atlas and the Genotype-Tissue Expression project were integrated, leading to the identification of 197 ER stress-associated differentially expressed genes and 1077 co-expressed lncRNAs. A prognostic 8-lncRNA model was developed using univariate/multivariate Cox regression and least absolute shrinkage and selection operator analysis. The model was validated by survival analysis (Kaplan–Meier and receiver operating characteristic curves), immune infiltration profiling (CIBERSORT and single-sample gene set enrichment analysis), and drug sensitivity analysis. Patients classified into the high-risk category showed significantly shorter overall survival (OS) (log-rank P < .001) and higher chemosensitivity to PI3K/mTOR inhibitors, whereas the low-risk group showed high immune activity (CD8+ T-cell infiltration and checkpoint expression) along with improved responsiveness to Wnt pathway inhibitors. The predictive capacity of the model (area under the curve, AUC: 0.806–0.856) exceeded that of conventional clinical parameters. Functional validation further revealed that LIPE-AS1, a representative high-risk lncRNA, promotes cervical cancer cell proliferation, migration, and invasion. These results introduce a novel ER stress-associated lncRNA signature with prognostic and therapeutic value, thus providing a potential basis for personalized immunotherapeutic and chemotherapeutic strategies in cervical cancer.

Background: Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but has encountered challenges in solid tumors. Macrophages, being a potentially effective therapeutic target, have led to the development of several therapeutic strategies due to their unique phagocytic function. This study aimed to develop an effective solid tumor immunotherapy strategy by combining CAR macrophages (CAR-Ms) targeting PD-L1 with CD47 antibody-armed oncolytic adenovirus (oAd-CD47). Methods: In this study, an adenoviral vector was employed to construct CAR-Ms that target PD-L1 and express IFN-γ. The phagocytic capacity and phenotype of CAR-Ms were tested in vitro. Two mouse tumor models with different immunogenicity were utilized to investigate the anti-tumor efficacy of CAR-Ms in vivo. Subsequently, the synergistic anti-tumor effects of CAR-M and oAd-CD47 and their underlying mechanisms were explored. Results: CAR-Ms exhibited enhanced phagocytic capacity and proinflammatory (M1) phenotype. These CAR-Ms significantly reduced tumor burden and extended overall survival in mice bearing CT26 colon cancer, a model characterized by high immunogenicity. Compared with CAR-Ms and oAd-CD47 monotherapy, this combination therapy (C + o) achieved superior antitumor efficacy in the CT26 and B16 melanoma mouse models, as well as in the ID8 peritoneal metastasis model. Notably, C + o treatment enhanced tumor-associated macrophage (TAM) phagocytosis and reduced the population of inhibitory immune cell subsets, thereby resulting in enhanced adaptive antitumor T-cell and neoantigen-specific T-cell immunity. Additionally, the synergistic antitumor effect of C + o was dependent on CD8⁺ T cells. Conclusion: The treatment strategy of CAR-Ms combined with oAd-CD47 provides a promising, novel and effective treatment method for individualized targeted therapy of solid tumors.

Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.

Background: High‐risk human papillomavirus (HPV), especially HPV16, is closely correlated with certain cancers. E6 and E7 proteins of HPV16 play critical roles in oncogenesis, making them optimal targets for treating HPV‐associated cancers. Here, we engineered an innovative vaccine, Ad‐E6/7‐HR, designed to evoke immune responses through the incorporation of self‐assembling heptad‐repeat 1 (HR1) and HR2 originated from Severe acute respiratory syndrome coronavirus 2.Methods: Ad‐E6/7‐HR was constructed utilising a replication‐defective human adenovirus serotype 5 vector and evaluated its immunogenicity and therapeutic efficacy in murine models. We verified the antitumour efficacy of the vaccine in TC‐1 subcutaneous and pulmonary models. Flow cytometry, enzyme‐linked immunospot assay, and immunofluorescence staining were used to assess the cellular immunogenicity of Ad‐E6/7‐HR.Results: Ad‐E6/7‐HR induced robust immune responses, significantly increasing antigen‐specific CD8⁺ T cells. The vaccine also enhanced memory T‐cell generation and induced potent cytokine secretion, as exemplified by interferon‐γ and tumour necrosis factor‐α. Ad‐E6/7‐HR conferred complete protection against tumour growth in the prophylactic model. In therapeutic settings, Ad‐E6/7‐HR significantly reduced tumour size and improved survival. Furthermore, Ad‐E6/7‐HR reshaped the tumour microenvironment by increased CD8⁺ T‐cell recruitment and reduced immunosuppressive cells, like myeloid‐derived suppressor cells and M2 macrophages, thereby enhancing antitumour immunity.Conclusions: By targeting HPV16 E6 and E7 proteins and leveraging the self‐assembling HR1 and HR2 sequences to enhance immune responses, Ad‐E6/7‐HR represented a promising candidate for preventing and treating HPV‐associated cancers. Further clinical investigation is warranted to evaluate its potential in human trials.

: Human papillomaviruses, particularly high-risk human papillomaviruses, have been universally considered to be associated with the oncogenesis and progression of various cancers. The genome of human papillomaviruses is circular, double-stranded DNA that encodes early and late proteins. Each of the proteins is of crucial significance in infecting the epithelium of host cells persistently and supporting viral genome integrating into host cells. Notably, E6 and E7 proteins, classified as oncoproteins, trigger the incidence of cancers by fostering cell proliferation, hindering apoptosis, evading immune surveillance, promoting cell invasion, and disrupting the balance of cellular metabolism. Therefore, targeting human papillomaviruses and decoding molecular mechanisms by which human papillomaviruses drive carcinogenesis are of great necessity to better treat human papillomaviruses-related cancers. Human papillomaviruses have been applied clinically to different facets of human papillomavirus-related cancers, including prevention, screening, diagnosis, treatment, and prognosis. Several types of prophylactic vaccines have been publicly utilized worldwide and have greatly decreased the occurrence of human papillomavirus-related cancers, which have benefited numerous people. Although various therapeutic vaccines have been developed and tested clinically, none of them have been officially approved to date. Enhancing the efficacy of vaccines and searching for innovative technologies targeting human papillomaviruses remain critical challenges that warrant continuous research and attention in the future.

Background: Although immunotherapy can reinvigorate immune cells to clear tumors, the response rates are poor in some patients. Here, CD47 antibody-engineered oncolytic viruses (oAd-αCD47) were employed to lyse tumors and activate immunity. The oAd-αCD47 induced comprehensive remodeling of the tumor microenvironment (TME). However, whether the acidic TME affects the antitumor immunotherapeutic effects of oncolytic viruses-αCD47 has not been clarified. Methods: To assess the impact of oAd-αCD47 treatment on the TME, we employed multicolor flow cytometry. Glucose uptake was quantified using 2NBDG, while mitochondrial content was evaluated with MitoTracker FM dye. pH imaging of tumors was performed using the pH-sensitive fluorophore SNARF-4F. Moreover, changes in the calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP activates-responsive element-binding proteins (CREB) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) signaling pathway were confirmed through western blotting and flow cytometry. Results: Here, we identified sodium bicarbonate (NaBi) as the potent metabolic reprogramming agent that enhanced antitumor responses in the acidic TME. The combination of NaBi and oAd-αCD47 therapy significantly inhibited tumor growth and produced complete immune control in various tumor-bearing mouse models. Mechanistically, combination therapy mainly reduced the number of regulatory T cells and enriched the ratio of M1-type macrophages TAMs (M1.TAMs) to M2-type macrophages TAMs (M2.TAMs), while decreasing the abundance of PD-1⁺TIM3⁺ expression and increasing the expression of CD107a in the CD8⁺ T cells. Furthermore, the combination therapy enhanced the metabolic function of T cells and macrophages by upregulating PGC1α, a key regulator of mitochondrial biogenesis. This metabolic improvement contributed to a robust antitumor response. Notably, the combination therapy also promoted the generation of memory T cells, suggesting its potential as an effective neoadjuvant treatment for preventing postoperative tumor recurrence and metastasis. Conclusions: Tumor acidic microenvironment impairs mitochondrial energy metabolism in macrophages and T cells inducing oAd-αCD47 immunotherapeutic resistance. NaBi improves the acidity of the TME and activates the CaMKII/CREB/PGC1α mitochondrial biosynthesis signaling pathway, which reprograms the energy metabolism of macrophages and T cells in the TME, and oral NaBi enhances the antitumor effect of oAd-αCD47.