Lung cancer is the leading cause of cancer mortality among people with HIV (PWH), with increased incidence and poor outcomes. This study explored whether the tumor microenvironment (TME) of HIV-associated non-small cell lung cancer (NSCLC) limits tumor-specific immune responses. With a matched cohort of NSCLC samples from PWH and from people without HIV (PWOH), we used imaging mass cytometry, a linear mixed-effects model, and an artificial intelligence-based (AI-based) PageRank mathematical algorithm based on spectral graph theory to demonstrate that HIV-associated tumors have differential distribution of tumor-infiltrating CD8+ and CD4+ T cells, enriched for the expression of programmed cell death 1 (PD-1) and lymphocyte-activating gene 3 (LAG3), as well as activation and proliferation markers. We also demonstrate higher expression of immunoregulatory molecules (PD-L1, PD-L2, B7-H3, B7-H4, IDO1, and VISTA) among tumor-associated macrophages. Discrimination of cells between tumors from PWH versus those from PWOH was confirmed by spectral graph theory with 84.6% accuracy. Furthermore, we noted differences in spatial orientation of immune cells within the TME of PWH compared with PWOH. Additionally, cells from PWH, compared with those from PWOH, exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines. In conclusion, our study demonstrates that the HIV-associated TME sustained a unique immune landscape, showing evidence of immune cells with enhanced immunoregulatory phenotypes and impaired antitumor responses, with implications for responses to immune checkpoint blocker therapies.

The close association between nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV) infection highlights the potential of therapeutic vaccination against viral antigens as an attractive immunotherapy for treating EBV+ NPC. Maximizing vaccine efficacy often requires selecting optimal T cell epitopes and incorporating co-treatment strategies. Here, we analyzed genomic mutations of 283 cancer-associated EBV strains and predicted epitopes with broad human leukocyte antigen (HLA) coverage from high-frequency nonsynonymous mutations. A polyepitope mRNA vaccine constructed from the predicted epitopes elicited antigen-specific T cell responses but showed suboptimal efficacy in tumor control in a PBMC-humanized mouse EBV+ NPC model. To enhance treatment efficacy, we developed an optimized system for expanding human natural killer (NK) cells with high purity and cytotoxicity as a co-treatment modality. Combined administration of mRNA vaccine and NK cells synergistically improved therapeutic efficacy by durably suppressing or eradicating NPC tumors in humanized mice. The concurrent treatment could improve the infiltration of both human T cells and NK cells into the tumor microenvironment and boost their effector functions. Our study suggests the combined therapeutic vaccination and NK cell therapy as a potential strategy for treating EBV+ NPC.
© 2025 The Author(s).

Folic acid has been associated with fetal development, especially in fetal immunity. Therefore, limited evidence regarding the effects of different folic acid supplementation of hepatitis B surface antigen (HBsAg) positive mothers in innate immunity in offspring. Herein, this study aimed to explore the association between folic acid supplementation and the innate immunity of neonates and the immunological efficacy of hepatitis B vaccine (HepB), which may provide insights that could inform pre-pregnancy health management in HBsAg-positive mothers.
It is an ambispective cohort study with 293 pairs of HBsAg-positive mothers-offspring in Taiyuan, Shanxi Province, China. Mothers were classified into three groups according to the time of starting folic acid supplementation, non-supplementation group, pre-pregnancy group and post-pregnancy supplementation group. Immunological indexes such as immune cells proportion and innate immune mediators in cord blood and anti-HBs in infants were measured. Differences in immunological indexes were analyzed by One-Way ANOVA test. Univariate and multivariate analyses were performed for factors associated with abnormal immunological indexes and potential confounders were adjusted.
The preconception folic acid group showed a significantly higher expression levels of STING (P = 0.005) and pNF-κB (P = 0.010) in cord blood along with higher anti-HBs titres (P = 0.006), when compared to both non-supplementation group and post-pregnancy supplementation group. Higher anti-HBs levels indicate a stronger immune response to HepB and may enhance protection against HBV infection during early life. Infants in the high pNF-κB expression group exhibited a significantly elevated seropositive rate of HepB compared to those in the low pNF-κB expression group (P = 0.037). There were no mediation effects and no moderation effects in this study, potentially due to the direct influence of folic acid supplementation on immune responses or the limited sample size.
In conclusion, our findings demonstrate that preconception folic acid supplementation may enhance HepB vaccine responsiveness in infants of HBsAg-positive mothers. Meanwhile, high pNF-κB expression in cord blood can increase seropositive rates in infants. This discovery has significant public health implications, as it may provide a simple and accessible intervention to improve vaccination outcomes and reduce HBV transmission in endemic regions.
Copyright © 2025 Lian, Men, Xu, Li, Li, Wang, Yao, Li, Qu, Feng and Wang.

In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.
Copyright © 2024. Published by Elsevier Inc.

The efficacy of chemotherapy varies significantly among patients with gastric cancer (GC), and there is currently no effective strategy to predict chemotherapeutic outcomes. In this study, we successfully establish 57 GC patient-derived organoids (PDOs) from 73 patients with GC (78%). These organoids retain histological characteristics of their corresponding primary GC tissues. GC PDOs show varied responses to different chemotherapeutics. Through RNA sequencing, the upregulation of tumor suppression genes/pathways is identified in 5-fluorouracil (FU)- or oxaliplatin-sensitive organoids, whereas genes/pathways associated with proliferation and invasion are enriched in chemotherapy-resistant organoids. Gene expression biomarker panels, which could distinguish sensitive and resistant patients to 5-FU and oxaliplatin (area under the dose-response curve [AUC] >0.8), are identified. Moreover, the drug-response results in PDOs are validated in patient-derived organoids-based xenograft (PDOX) mice and are consistent with the actual clinical response in 91.7% (11/12) of patients with GC. Assessing chemosensitivity in PDOs can be utilized as a valuable tool for screening chemotherapeutic drugs in patients with GC.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.