Ying Luo

Stem-like T cells promote the efficacy of immunotherapy and are heterogeneous in stemness, with long-term (LT) stem-like T cells at the apex of this hierarchy. How the stemness hierarchy is regulated in chimeric antigen receptor (CAR) T cells and how it affects antitumor function are unclear. Here we show that BACH2 dose-dependently regulates LT stem-like differentiation and antitumor immunity of CAR T cells. LT stem-like CAR T cells that appear before infusion and re-emerge after tumor clearance have superior antitumor immunity and the greatest BACH2 expression. BACH2 promotes the antitumor response of CAR T cells and the LT stem-like transcriptional program. Temporal and quantitative induction of BACH2 expression in CAR T cells during manufacturing using chemical switches fine-tunes the degree of stemness and imprints greater control of solid tumors. Together, these data show that BACH2 dosage defines stemness hierarchy in CAR T cells and can be temporally and tunably controlled to optimize differentiation and antitumor efficacy.

Background: Arboviral infections impose significant public health challenges globally, yet routine surveillance typically captures only symptomatic infections, underestimating the true extent of exposure. Insights into how regional and demographic factors influence population immunity are essential for targeted surveillance and prevention, but such multidimensional insights remain limited. This study aimed to quantify population-level arboviral sero exposure and delineate the effects of regional and demographic factors on immunity to inform targeted surveillance and prevention. Methods: We utilized a programmable phage display platform, ArboScan, which evaluates antibody binding to overlapping peptides that represent the proteomes of 691 human and zoonotic arboviruses. We profiled baseline antibody reactivity in serum samples from 400 healthy individuals, collected before the dengue outbreaks reported in Hainan in 2019. Antibody reactivity was quantified as normalized fold-change (FC) values relative to negative controls, and analyzed by region, sex, and age. Normality was assessed using the Shapiro-Wilk test. Two-group comparisons were conducted using independent two-sample t tests for normally distributed data or Mann-Whitney U tests otherwise; comparisons among > 2 groups were performed using One-way Analysis of Variance for normally distributed data. Results: Regional ranking by mean product fold change (MPFC) showed northern enrichment for bluetongue virus (MPFC = 3.56), whereas southern cohorts were enriched for mosquito-borne arboviruses-dengue virus (MPFC = 3.54), Alagoas vesiculovirus (MPFC = 3.50), and Venezuelan equine encephalitis virus (MPFC = 3.39). Females exhibited higher FC than males for selected arboviral families ( P < 0.001). By family-level analysis, Flaviviridae , Togaviridae , and Phenuiviridae showed no age-stratified differences ( P > 0.05). High fold-change values were detected for non-arboviral viruses such as human cytomegaloviruses and human adenoviruses across all regions. Conclusions: Our findings reveal distinct regional and demographic patterns of arboviral antibody reactivity in China, reflecting differing histories of exposure and potentially informing region-specific surveillance strategies. The stable antibody levels across age groups, together with higher fold-change values in females, underscore the influence of biological and social factors on arboviral immunity. The ArboScan platform, and programmable peptide display platforms in general, offer a scalable approach to characterize population-level immunity and could enhance early detection and public health preparedness in arbovirus-endemic areas. Graphical

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. In this study, using joint single-cell transcriptome and T-cell receptor profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node (LN) in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes upregulated gene signatures of T-cell activation and exhaustion compared with those recognizing other tumor antigens. In the tumor-draining LN, we identified TCF1+TOX− stem cell memory T cells (TSCM), TCF1+TOX+ progenitor exhausted T cells (TPEX), and TCF1−TOX+ effector-like exhausted CD8+ T cells (TEX) subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared with clones biased toward TEX, TPEX, or TSCM. The TPEX subset had the greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point in which neoantigen-specific clones exited the LN and differentiated into TEX tumor-infiltrating lymphocytes. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the LN negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitors by patients with cancer. In conclusion, we have identified a transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in patients with cancer.

Background: In China, research on transition readiness among adolescents with chronic diseases remains exploratory. Cultural and healthcare system differences limit the applicability of Western findings. This study investigates the effects of self-efficacy and willingness to engage in healthcare on transition readiness, aiming to develop culturally informed interventions for the Chinese context. Methods: A cross-sectional study recruited 205 adolescents from a tertiary hospital in Wuhan through convenience sampling from March to October 2023. The study used validated scales to evaluate the following indicators: transition readiness (using The Self-Management and Transition to Adulthood with Rx = Treatment (STARx) Questionnaire), self-efficacy (through the General Self-Efficacy Scale), and healthcare engagement (using the questionnaire of willingness to engage in healthcare). Data analysis was conducted using SPSS 25.0 software and processed through methods such as independent sample t-test, one-way analysis of variance, pearson correlation analysis and multiple linear regression. Results: The overall level of transition readiness among adolescents with chronic diseases was moderate (mean score = 3.19 ± 0.58). Adolescents aged 13–15 years (β = 0.210, P = 0.003) and those over 15 years (β = 0.376, P < 0.001), along with self-efficacy (β = 0.229, P = 0.001) and willingness to engage in healthcare (β = 0.234, P < 0.001), were identified as independent positive predictors of transition readiness among adolescents with chronic diseases. Conversely, hemophilia (β= -0.350, P = 0.001), recurrent disease (β= -0.120, P = 0.037), disease deterioration (β = -0.155, P = 0.009), and maternal caregiving (β = -2.574, P = 0.011) emerged as significant negative predictors of transition readiness. Conclusions: This study reveals the key factors affecting the transition readiness of adolescents with chronic diseases, and emphasizes that a multidimensional and sustainable transition support system should be constructed from psychological empowerment, family involvement and individual differences to provide a basis for improving their long-term health management ability and quality of medical care interface.

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. In this study, using joint single-cell transcriptome and T-cell receptor profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node (LN) in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes upregulated gene signatures of T-cell activation and exhaustion compared with those recognizing other tumor antigens. In the tumor-draining LN, we identified TCF1+TOX− stem cell memory T cells (TSCM), TCF1+TOX+ progenitor exhausted T cells (TPEX), and TCF1−TOX+ effector-like exhausted CD8+ T cells (TEX) subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared with clones biased toward TEX, TPEX, or TSCM. The TPEX subset had the greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point in which neoantigen-specific clones exited the LN and differentiated into TEX tumor-infiltrating lymphocytes. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the LN negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitors by patients with cancer. In conclusion, we have identified a transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in patients with cancer.

Introduction Immunological niches in tumor microenvironments (TME) are spatially organized funct ional units where tumor cells interact with immune and stromal components through dynamic molecular networks[1]. These specialized microdomains exhibit dual functionality: while capa ble of supporting anti-tumor immunity through immune cell activation, they frequently evolve immunosuppressive properties that enable immune evasion and therapy resistance[2]. Emergi ng evidence reveals that niche characteristics significantly influence immunotherapy response s, with distinct spatial architectures associated with treatment sensitivity or resistance across c ancer types[3]. Understanding these regulatory mechanisms provides critical insights for deve loping strategies to reprogram immunosuppressive niches therapeutically. Decoding Niche Formation: Cellular and Molecular Architects Immunological niches within tumors emerge through coordinated interactions between t hree fundamental components: (1) tumor cells displaying antigenic and metabolic heterogenei ty, (2) immune populations (CD8+ T cells, tumor-associated macrophages [TAMs], dendritic c ells [DCs]), and (3) stromal elements (cancer-associated fibroblasts [CAFs], extracellular matr ix [ECM], vasculature). These components communicate through cytokine-chemokine networ ks (e.g., IFN-γ-mediated immune activation versus TGF-β-driven suppression) and direct cell-contact signals (e.g., PD-1/PD-L1 checkpoint interactions) to collectively regulate anti-tumor i mmunity[2; 4]. At the cellular level, stromal components - particularly CAFs - have been identified as k ey architectural regulators[5]. Single-cell multi-omics approaches have enabled precise charac terization of CAF heterogeneity. For instance, in colon adenocarcinoma, an 11-gene CAF sign ature effectively stratified patients into high-and low-risk groups, with the high-risk group ex hibiting greater immune infiltration yet paradoxically lower drug sensitivity [6]. Similarly, in t riple-negative breast cancer (TNBC), Ding et al.[7] established a prognostic model where high -risk patients showed increased stromal CAF and endothelial cells infiltration and poorer clini cal outcomes. At the molecular level, pathway activation analyses reveal critical mediators of niche fu nctionality[8]. A pan-cancer study demonstrated that EGFR pathway activation drives immuno therapy resistance through an EGFR-related gene signature (EGFR.Sig), which correlates with elevated exhaustion markers (TIM-3, LAG-3) and immunosuppressive ligands (PD-L1, CD4 7) [9]. The convergence of these molecular and cellular pathways underscores the need for mu ltidimensional therapeutic approaches targeting niche formation at multiple levels, a direction that may overcome therapeutic resistance and improve clinical outcomes. Biomarkers: From Niches to Clinical Tools Beyond mechanistic insights, translating immunological niches into clinically actionabl e biomarkers has become a critical frontier in precision oncology[10]. Systemic inflammation indices derived from peripheral blood have demonstrated clinical utility as non-invasive niche proxies. As demonstrated in our Research Topic, these indices provide valuable insights for cl inical prognosis and treatment strategies: In esophageal cancer, the systemic immune-inflamm ation index (SII) was identified as an independent prognostic factor for recurrence-free surviv al after esophagectomy [11]. In breast cancer, elevated preoperative systemic inflammation res ponse index (SIRI) served as an independent risk factor for disease-free survival [12]. Similarl y, in locally advanced cervical cancer, the pan-immune-inflammation value (PIV) was establis hed as a robust and independent prognostic factor significantly correlated with overall surviva l and disease-free survival [13]. Niche-informed molecular subtyping is transforming patient stratification: In acute mye loid leukemia, molecular subtyping based on ligand-receptor (LR) pairs has unveiled distinct i mmune landscapes and prognostic differences. A scoring model termed LR.score effectively st ratifies patients by survival risk and reflects the degree of T-cell dysfunction, offering insights into niche-driven immune dysregulation and therapy resistance [14]. In melanoma, aryl hydro carbon receptor (AhR)-related gene signatures (MAP2K1, PRKACB, KLF5, and PIK3R2) hav e been identified as a potential prognostic tool, strongly associated with immune infiltration an d tumor progression, providing a robust prognostic framework and potential therapeutic target s [15]. These advances collectively represent a paradigm shift in cancer management, where ni che-derived biomarkers are moving from research tools to clinical implementation. By capturi ng the complex interplay between tumor cells and their microenvironment, these biomarkers e nable more precise patient stratification and treatment selection[16]. Therapeutic Strategies: Rewriting Niche Rules Although biomarkers yield valuable insights into niche dynamics, converting these findi ngs into effective treatments remains a major challenge. To bridge this gap, therapeutic develo pment is increasingly directed at reprogramming the tumor–immune interface by modulating n iche biology through diverse approaches[17]. Targeting immune-related molecules remains a well-established and effective therapeuti c approach. For example, RAC3 has been shown to drive tumor aggressiveness and immune e vasion in bladder cancer, positioning it as a potential dual biomarker and therapeutic target[18]. Stromal remodeling strategies are also gaining prominence. Clinical translation is alread y evidenced by the success of anlotinib (an anti-angiogenic agent) combined with anti-PD-L1 therapy in high-grade serous ovarian cancer. This combination therapy inhibits angiogenesis, e nhances immune infiltration while simultaneously reinvigorating exhausted T cells [19], demo nstrating the...