Cell Reports Medicine
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2025
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IF 10.6
Feixiang Wang,Rujuan Bao,Shuiyu Xu,Wenyan Li,Haiyan Huang,Runchang Li,Xinyu Ding,Yuerong Zhang,Xiaoyan Yu,Qiaoqiao Han,Xian Du,Jie Wan,Song Li,Yichuan Xiao,Ren Zhao,Xingang Cui,Youqiong Ye,Jiayuan Sun,Junke Zheng,Guo-Qiang Chen,Qiang Zou
T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8 + T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8 + T cells increases with age, leading to a weak antitumor effect. Moreover, decreased levels of adipocyte-derived leptin are an indispensable factor for CD8 + T cell aging. Leptin signaling prevents p38-dependent CD8 + T cell senescence. Furthermore, plasma leptin levels are negatively related to intratumoral CD8 + T cell senescence in cancer patients. Our findings identify an unappreciated interplay between metabolic perturbation and T cell aging and suggest that modulating adipocyte-derived leptin levels may be a promising therapeutic strategy for older cancer patients.
研究领域:
免疫学
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癌症生物学
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细胞生物学
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老年学
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代谢研究
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高影响因子
Cell Reports
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2026
·Vol. 45
·期 2
·116933
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IF 6.9
Chunyu Feng,Su-Ran Li,Xiaoshuai Xu,Zihan Dang,Zihan Jiang,Erhui Jiang,Zhengjun Shang
Summary The role of neurotransmitters in suppressing anti-tumor immunity has garnered increasing attention. While glutamate has been extensively studied in neurological diseases, its potential role in regulating anti-tumor immunity, particularly in the context of neoadjuvant immunochemotherapy, remains underexplored. In this study, we find that glutamate levels are elevated in the plasma of head and neck squamous cell carcinoma (HNSCC) patients. The METTL3/m6A/CD98 axis in cancer-associated fibroblasts (CAFs) is a key driver of glutamate secretion. Glutamate induces CD8 + T cell exhaustion through SLC1A3 and impairs the formation of immune memory in secondary lymphoid structures. Additionally, glutamate promotes ferroptosis resistance in HNSCC. Notably, glutamate depletion enhances the efficacy of neoadjuvant immunochemotherapy. Our findings provide insights into how the METTL3/m6A/CD98 axis-mediated regulation of glutamate efflux may sensitize HNSCC to neoadjuvant immunochemotherapy.
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Science Immunology
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2025
·Vol. 10
·期 108
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IF 16.3
Limin Cao,Li Wang,Zhihong Li,Xia Wei,Jinqiu Ding,Chun Zhou,Xia Chen,Zhicheng Huang,Zhugui Shao,Junchen Shen,Hongfei Lou,Keqing Zhao,Yuwei Huang,Yuanqin Yang,Han Liu,Yumeng Sun,Junling Niu,Shan Jiang,Rong Lu,Longhai Tang,Xiaoming Zhang,Haibing Zhang,Yichuan Xiao,Jianfeng Chen,Shixin Ma,Chengjiang Gao,Guangxun Meng,Li Liu,Zhaozhu Qiu,Haopeng Wang,Liufu Deng,Youqiong Ye,Xin-Ming Jia,Huabin Li,Hui Xiao
The volume-regulated anion channels (VRACs) transport osmolytes, neurotransmitters, and cyclic GMP-AMP (cGAMP) across the cell membrane to regulate cell volume and host defense. We report that the leucine-rich repeat–containing 8A/C (LRRC8A/C) VRAC plays a crucial role in immune responses to radiotherapy and chemotherapy for cancer. VRACs transfer cGAMP from irradiated cancer cells to infiltrating CD4 and CD8 T cells, thus enhancing their effector functions. TCR signaling acts as a physiological signal to open the VRAC pore through phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and reactive oxygen species (ROS). This allows the rapid uptake of cGAMP and STING activation in mouse and human T cells and induction of interferon-α/β, which up-regulate granzymes and IFN-γ in CD8 T cells. Inhibition of the extracellular hydroxylases CD39 and ENPP1 maintains extracellular ATP and cGAMP, which promotes VRAC-enhanced CD8 T cell anticancer function. Thus, the transfer of cGAMP to T cells by VRACs may be a strategy that can be targeted in future cancer therapies.
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ACTA PHARMACOLOGICA SINICA
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2026
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IF 10.4
Li Ju-fei,Wang Hao,Kang Ling,Xu Cheng-cheng,Liu Yuan-chun,Li Zi-xuan,Lin Shao-hao,Wang Ming-zhi,Xu Xiao-min,Wang Pei-pei,Yin Wan-chao,Zhou Yu-bo,Zhou Yu,Li Jia
Metabolic hijacking of tryptophan (Trp) via the IL4I1-AHR axis is a pivotal immune evasion mechanism in cancers, yet therapeutic strategies to disrupt this pathway remain unexplored. Here, we report the identification of ZY-MY-111, a selective small-molecule inhibitor of interleukin-4-induced-1 (IL4I1), through an in-house compound library screening and structural optimization. ZY-MY-111 exhibits potency (IC 50 = 1.86 ± 0.13 μM) in blocking IL4I1-mediated oxidative deamination. Mechanistically, ZY-MY-111 acts as a mixed-type inhibitor, competitively occupying the catalytic pocket of IL4I1 and disrupting Trp-AHR signaling in cells. Functionally, ZY-MY-111 promotes T cell proliferation, enhancing immune responses against the tumor cells. In syngeneic tumor models, ZY-MY-111 achieved 49% tumor growth inhibition in CT26 colon carcinoma ( P < 0.001) and 56% tumor growth inhibition in A20 lymphoma ( P < 0.001) by remodeling the immunosuppressive microenvironment: increasing CD8 + /CD4 + T cell ratios, reducing myeloid-derived suppressor cells (MDSCs, 59% decrease), and enhancing effector memory T cell infiltration. Our findings position IL4I1 inhibition as a potential strategy to restore anti-tumor immunity.
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Cancer Immunology Research
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2025
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IF 8.2
Liu Chuwei,Liang Heng,Wang Peipei,Xiao Min,Zheng Yuyan,Yan Shijia,Deng Yuan,Liu Ruonian,Wan Arabella H.,Wang Zhi,Lu Xiongbin,Song Wu,He Weiling,Wan Guohui
Immune checkpoint blockade (ICB) has transformed colorectal cancers (CRCs) therapy, yet the majority of microsatellite-stable (MSS) CRCs remain refractory due to insufficient tumor-immune cell crosstalk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. Here, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in CRC, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a non-inflamed (“cold”) tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized MSS CRCs to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1’simpact on tumor-immune interactions, and showed that it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in CRC.
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PHYTOMEDICINE
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2026
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IF 11.3
Fei Lin,Jinyu Wang,Yue Han,Dehong Zhang,Bo Wu,Tingxu Yan,Ying Jia
PE fraction of WTX alleviates colitis via microbiota-linoleic acid-CD8⁺ T cell axis. • PE enriches Bacteroidota , suppresses Proteobacteria and linoleic acid metabolism. • ALOX5/PTGS2 downregulation reduces pathogenic CD8⁺ T-cell infiltration. • Luteolin, Isoalantolactone, Citreorosein identified as key PE constituents. Background Wei-Tong-Xin (WTX), derived from the Hua Tuo Zhong Cang Jing , has been demonstrated to exert therapeutic effects against gastric ulcers and gastritis, with well-established anti-inflammatory properties. However, its potential role in intestinal inflammation has not yet been investigated. Purpose To evaluate the therapeutic efficacy of WTX in dextran sulfate sodium (DSS)-induced colitis in mice and to elucidate its underlying pharmacological mechanisms while identifying its active components. Methods Mice with DSS-induced colitis were treated with WTX extracts. The primary active fraction of WTX was identified by screening intestinal injury and hematological indicators. Integrated 16S rRNA sequencing, serum metabolomics, and network pharmacology analyses were employed to investigate the therapeutic mechanisms. Specifically, serum metabolomics identified linoleic acid (LA) metabolism as the major metabolic pathway regulated by the petroleum ether (PE) fraction, whereas network pharmacology linked PE-derived constituents to colitis-related targets and identified ALOX5 and PTGS2 as key nodes connecting PE with LA metabolism. These findings were subsequently validated using LA supplementation and pseudo-germ-free mouse models. Results The PE fraction significantly alleviated colitis symptoms, including reduced disease activity index scores, attenuation of colon shortening, improved intestinal mucosal barrier integrity, and decreased CD8⁺ T-cell infiltration in the spleen, colon, and mesenteric lymph nodes. PE also reshaped the gut microbiota by modulating the abundance of Bacteroidota and Proteobacteria, reduced the levels of unsaturated fatty acids, particularly those involved in LA metabolism, and downregulated the expression of ALOX5 and PTGS2. Fecal microbiota transplantation produced comparable therapeutic effects, whereas LA supplementation reversed the protective effects of PE. Conclusion PE alleviates colitis by remodeling the gut microbiota, promoting the dominance of Bacteroidota, inhibiting LA metabolism through the ALOX5/PTGS2 pathway, and suppressing the activation of pathogenic CD8⁺ T cells. These effects collectively preserve intestinal barrier integrity and mitigate the progression of colitis. Download: Download high-res image (348KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·Vol. 24
·期 1
·382
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IF 15
Jiang Zhou,Li Yuning
Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide, and the limited efficacy of immunotherapy due to treatment resistance underscores the urgent need for new therapeutic strategies. In the present study, CD93-targeted poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating resveratrol (CD93-NPs@RSV) were developed to remodel the metabolic fitness of CD8 + tumor-infiltrating lymphocytes. The nanoparticles were precisely engineered and characterized using dynamic light scattering, transmission electron microscopy, and in vivo imaging, which confirmed their stability and tumor-targeting capability. Mechanistic studies revealed that CD93-NPs@RSV suppressed CD93 expression, facilitated apoptosis-inducing factor (AIF) mitochondrial translocation, and activated oxidative phosphorylation (OXPHOS), thereby enhancing T cell function in the tumor microenvironment. Transcriptomic and proteomic analyses further confirmed regulation of the CD93-AKT-PAK5-AIF signaling axis. In a Lewis LC model, CD93-NPs@RSV significantly inhibited tumor progression and displayed strong synergy with anti-PD-1 therapy, resulting in improved survival outcomes. Collectively, our study demonstrates that CD93-NPs@RSV provide a powerful nanotechnology-driven approach to reverse immunotherapy resistance by reprogramming T cell metabolism. These findings establish a promising paradigm for precision cancer immunotherapy and underscore the translational potential of targeted nanomedicine in overcoming therapeutic bottlenecks in LC. Graphical abstract The alternative text for this image may have been generated using AI.
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Experimental Hematology & Oncology
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2025
·Vol. 14
·期 1
·1-17
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IF 13.5
Ren Xueting,Wu Jinpeng,Li Jing,Zhai Zhen,Li Xiang,Guan Feng,Wang Meng,Ma Xiaobin,Tan Zengqi,Kang Huafeng,Lin Shuai
Background The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.Methods This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8+ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.Results MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8+ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8+ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs’ ability to block CD8+ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8+ T cell abundance and activity, achieving a more effective antitumor response in vivo.Conclusion sThese findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8+ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.
研究领域:
癌症生物学
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免疫学
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生物化学
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糖生物学
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分子生物学
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高影响因子
Theranostics
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2025
·Vol. 15
·期 10
·4481
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IF 13.3
Yupeng Sun,Rui Li,Yike Cai,Yan Liu,Peiyuan Wang,Ming Wu,Xiaolong Zhang,Naishun Liao,Cuilin Zhang,Aixian Zheng,Haipo Xu,Rui Zeng,Yongyi Zeng,Xiaolong Liu
Tumor-infiltrating CD8 + T cells and programmed death-1 (PD1) levels are critical indicators for tumor immunophenotyping and therapeutic decision-making. Noninvasive optical imaging in the second near infrared window (NIR-II) is particularly well-suited for investigating the biological processes within tumors in live mammals, thanks to its deep-tissue penetration and superior spatiotemporal resolution. However, in vivo NIR-II imaging has primarily been restricted to a single probe at a time. Methods: Herein, we developed a two-plex NIR-II molecular imaging method utilizing the non-overlapping fluorescence emission of indocyanine green (ICG) in the NIR-IIa window (1000-1200 nm) and PbS/CdS core-shell quantum dots (QDs) in the NIR-IIb window (1500-1700 nm). By integrating PD1 aptamer-labeled ICG (ICG-Apt-PD1, targeting PD1) and CD8 aptamer-labeled QDs (QDs@Apt-CD8, targeting CD8 + T cells), our two-plex NIR-II molecular imaging enabled simultaneous and noninvasive monitoring of the number of CD8 + T cells and PD1 levels in tumors. Results: QDs@Apt-CD8 demonstrated the excellent ability for in vivo imaging of tumor infiltrating CD8 + T cells, owing to its strong NIR-IIb luminescence and the high selectivity and specificity. This two-plex in vivo molecular imaging allowed for dynamic monitoring for PD1 levels and the number of CD8 + T cells in tumors. We observed the heterogeneous bio-distributions of PD1 and CD8 + T cells across different tumor types and revealed the tumor immunophenotypes. Moreover, our findings indicated that the low PD1 and high CD8 + T cells levels in tumors predicted a better anti-tumor effect. Conclusions: Such in vivo noninvasive NIR-II molecular imaging would complement ex vivo biopsy-based diagnostic techniques, and it could contribute to developing an in vivo tumor immune-scoring algorithm to offer a more precise prediction for immunotherapeutic response.
研究领域:
生物医学工程
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肿瘤免疫学
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分子影像学
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PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Shijia Lu,Chenxiao Zhang,Huiru Wu,Junjie Wang,Jinglong Wang,Limei Zhao,Tianyang Ren,Guofei Li
Liver cancer is one of the malignant tumors with high morbidity and mortality worldwide and lacks effective clinical treatments. CD8 + T cell-based immunotherapy is the most promising option for the treatment of liver cancer, but its application is severely limited by low infiltration and functional exhaustion of CD8 + T cells in liver cancer tissues. To overcome this problem, in this study, pH/matrix metalloproteinase-9 (MMP-9) dual-responsive liposomes were constructed and co-loaded with a galectin-3 (Gal-3) inhibitor, GB1107, a programmed death receptor 1 (PD-1) inhibitor, BMS1166, and an androgen receptor (AR) antagonist, enzalutamide, for immunotherapy studies in liver cancer. Specifically, the co-loaded liposomes (GBE@LP) were produced with a one-two punch targeting antitumor immunity. First, GBE@LP exhibited prolonged circulation in the blood and accumulated in liver cancer tissues through the enhanced permeability and retention effect due to the presence of surface polyethylene glycol. After entering liver cancer tissues, GBE@LP responded to the low pH and overexpression of MMP-9 in the microenvironment to promote the release of GB1107, BMS1166, and enzalutamide, thus, realizing the intelligent release of drugs targeting liver cancer. Upon reaching liver tumor tissues, GB1107 can inhibit overexpressed Gal-3 to transform liver cancer from a “cold” to a “hot” tumor and enable deep penetration by CD8 + T cells. In addition, BMS1166 and enzalutamide inhibit PD-1 and AR in CD8 + T cells, reversing CD8 + T cell exhaustion and enhancing their killing activity. In vivo and in vitro experiments confirmed the significant antitumor effects of GBE@LP in liver cancer. These results indicate that our strategy is expected to reverse the “cold” tumor and immune exhaustion state of liver cancer, which not only improves therapeutic efficacy, but also provides a new paradigm for the exploration of liver cancer immunotherapy.
研究领域:
肿瘤学
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药理学
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免疫学
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Bioactive Materials
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2024
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IF 18
Daping Xie,Congwei Han,Chonghao Chen,Zhencheng Liao,Senio Campos de Souza,Yiming Niu,João F. Mano,Lei Dong,Chunming Wang
Cancer vaccination holds great promise for cancer treatment, but its effectiveness is hindered by suboptimal activation of CD8 + cytotoxic T lymphocytes, which are potent effectors to mediate anti-tumor immune responses. A possible solution is to switch antigen-presenting cells to present tumor antigens via the major histocompatibility complex class I (MHC-I) to CD8 + T cells – a process known as cross-presentation. To achieve this goal, we develop a three-dimensional (3D) scaffold vaccine to promote antigen cross-presentation by persisted toll-like receptor-2 (TLR2) activation after one injection. This vaccine comprises polysaccharide frameworks that “hook” TLR2 agonist (acGM) via tunable hydrophobic interactions and forms a 3D macroporous scaffold via click chemistry upon subcutaneous injection. Its retention-and-release of acGM enables sustained TLR2 activation in abundantly recruited dendritic cells in situ , inducing intracellular production of reactive oxygen species (ROS) in optimal kinetics that crucially promotes efficient antigen cross-presentation. The scaffold loaded with model antigen ovalbumin (OVA) or tumor specific antigen can generate potent immune responses against lung metastasis in B16-OVA-innoculated wild-type mice or spontaneous colorectal cancer in transgenic Apc Min/+ mice, respectively. Notably, it requires neither additional adjuvants nor external stimulation to function and can be adjusted to accommodate different antigens. The developed scaffold vaccine may represent a new, competent tool for next-generation personalized cancer vaccination.
研究领域:
免疫学
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肿瘤学
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生物医学工程
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Acta Pharmaceutica Sinica B
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2023
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IF 14.5
Siqin He,Lulu Wang,Dongxu Wu,Fan Tong,Huan Zhao,Hanmei Li,Tao Gong,Huile Gao,Yang Zhou
A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8 + T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β -cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β -carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.
研究领域:
肿瘤学
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药剂学
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免疫学
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高影响因子
危险品化学品经营许可证（带存储）