Oncology
Abstract
Immune evasion is a major obstacle ahead of pancreatic cancer therapy. Recent data implicate pro-inflammatory macrophages in the progression of pancreatic ductal adenocarcinoma (PDAC) and its therapeutic response. However, whether or which of the pro-inflammatory macrophage subtypes play a crucial role in the immune escape of PDAC remains unclear. Here we identify a population of CD138+ tumor-associated macrophages (TAMs), characterized by their pro-inflammatory and neutrophil-chemotactic activity, which undergo significant expansion in both PDAC patients and mouse models. These cells are elicited by a local synergy between IL-34-syndecan-1 and PGE2-EP2 signaling and are associated with immune evasion and poor clinical outcomes in patients, while also promoting immune escape and disease progression in mouse models. Mechanistically, CD138+ TAMs establish a feedforward loop with immunosuppressive Siglec-F+ neutrophils, which exhibit elevated PGE2 expression, via the secretion of Saa3 and Cxcl1. Targeting CD138+ TAMs by disrupting IL-34-syndecan-1 signaling with anti-IL-34 neutralizing antibodies significantly suppresses PDAC progression, especially when combined with anti-PD-1 antibodies. Together, our study elucidates a CD138+ TAM-Siglec-F+ neutrophil axis that drives immune escape in PDAC and proposes a therapeutic strategy that integrates IL-34-syndecan-1 signaling blockade with anti-PD-1 immunotherapy for the treatment of PDAC.
Authors
Chao Wang, Qi Zhang, Jinyan Huang, Fangyu Lin, Danyang Zhao, Youling Mu, Junshuo Tong, Jinping Li, Yingjiqiong Liang, Tao Zeng, Fukang Shi, Hang Shen, Tingting Lu, Tingbo Liang
Abstract
Lysine-specific demethylase 1 (LSD1; KDM1A) orchestrates context-dependent chromatin programs, yet its role in epithelial immunity remains largely unknown. Here, we identify LSD1 as a central brake on retinoid- and AP-1–driven enhancer activation in epidermis and demonstrate that its inhibition induces anti-tumor immunity. While epidermal LSD1 is required during development, acute loss or topical inhibition in adult skin is tolerated and triggers coordinated expression of retinoic acid signaling, lipid remodeling, and chemokine induction pathways. CUT&RUN profiling reveals that LSD1 occupies enhancer regions enriched for AP-1 motifs at retinoid metabolism, lipid homeostasis, and immune genes. LSD1 loss increases H3K4me1/2 and gene activation at these sites, licensing a poised AP-1–retinoid program. Single-cell spatial analyses show that discrete keratinocyte subsets initiate retinoid signaling to recruit dendritic cells and activate CD4+ T cell responses. Topical LSD1 inhibition suppresses cutaneous squamous cell carcinoma in two models while amplifying keratinocyte–immune crosstalk. Functional perturbations reveal that retinoid signaling partially contributes, whereas CD4+ T cells are essential for tumor control. These findings define LSD1 as a master repressor of epithelial immune competence and nominate LSD1 inhibition as a therapeutic strategy to activate retinoid–AP-1 enhancer circuits and drive CD4-dependent tumor immunity in skin cancer.
Authors
Nina Kuprasertkul, Alyssa F. Moore, Carina A. D'souza, Julia Chini, Eun-Kyung Ko, Sijia Huang, Shuo Zhang, Ashley S. Anderson, Shaun Egolf, Laura V. Pinheiro, Alison Jaccard, Claudia T. Magahis, Lydia Bao, Yann Aubert, Cyria R. Olingou, Stephen M. Prouty, Donna Brennan-Crispi, David A. Hill, John T. Seykora, Kathryn E. Wellen, Brian C. Capell
Abstract
Obesity-linked steatosis is a significant risk factor for hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying the transition from Metabolic dysfunction-associated steatotic liver disease (MASLD) to HCC remains unclear. We explored the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme, in chronic liver disease. Hepatocyte-specific NgBR deletion in mice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Similarly, liver-specific knockout of DHDDS (D-LKO) NgBR’s cis-PTase partner and a knock-in model carrying a human NgBR mutation that impairs cis-PTase activity developed HCC under high-fat diet conditions, although with lower penetrance. Single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Mechanistically, NgBR deficiency promotes excessive hepatic TAG accumulation by enhancing lipid uptake and impairing very-low-density lipoprotein (VLDL) secretion. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in TAG synthesis, abrogates diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish cis-PTase as a critical suppressor of MASLD-HCC conversion and suggest DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in advanced metabolic dysfunction-associated steatohepatitis (MASH).
Authors
Abhishek K. Singh, Balkrishna Chaube, Kathryn M. Citrin, Joseph Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C. Lowery, Sonal Shree, Keira E. Mahoney, Nabil E. Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T. Ross, Stacy A. Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A. Grabińska, William C. Sessa
Abstract
BACKGROUND. Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 axis have revolutionized metastatic non–small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood. METHODS. In this biomarker study involving 103 patients with mNSCLC—including 81 patients who received ICI treatment—we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex immunohistochemistry platform built for in-depth dissection of the TME. RESULTS. Among various types of intratumoral lymphocytes including T-helper 1 cells, regulatory T cells, and natural killer cells, only CD8+ T cells (TILs) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis. CONCLUSION. Our study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies. TRIAL REGISTRATION. Not applicable because this is a retrospective study. FUNDING. Osaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.
Authors
Kohsuke Isomoto, Koji Haratani, Takahiro Tsujikawa, Shuta Tomida, Yusuke Makutani, Masayuki Takeda, Kimio Yonesaka, Kaoru Tanaka, Tsutomu Iwasa, Kazuko Sakai, Kazuto Nishio, Akihiko Ito, Kazuhiko Nakagawa, Hidetoshi Hayashi
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) benefit homologous recombination-deficient (HRD) malignancies, yet resistance remains a major challenge. Leveraging specimens from a prospective neoadjuvant niraparib monotherapy trial in treatment-naïve high-grade serous ovarian cancer, we integrated PhenoCycler-Fusion spatial profiling, scRNA-seq, and multiplex immunohistochemistry to identify two therapeutic-modulated cellular neighborhoods: an IFN+ tumor cell-enriched niche that expands in resistant lesions and a tumor-associated macrophage (TAM)-enriched niche that persists but acquires enhanced immunosuppressive features. Mechanistically, sustained tumor cell-derived IFN induced osteopontin (SPP1) expression in TAMs via STAT signaling, creating immunosuppressive niches enriched in Tregs and myofibroblastic cancer-associated fibroblasts with intensified cell-cell interactions. SPP1 directly suppressed T cell signaling and effector function. High baseline SPP1+ cells predicted lower response rate (30.0% vs 76.2%, P = 0.021) and shorter progression-free survival (median 13.5 vs 28.3 months, P = 0.0006). In HRD mouse models, SPP1 blockade restored PARPi sensitivity, reversed acquired resistance, and enhanced T cell cytotoxicity—effects abrogated in immunodeficient mice, confirming immune dependence. These data establish a spatial IFN–SPP1 axis whereby persistent tumor cell IFN reprograms TAMs to promote PARPi resistance, position SPP1 as a key therapeutic target and prognostic biomarker for this therapy, and underscore therapeutic potential of microenvironment-targeted strategies to overcome PARPi resistance.
Authors
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
Abstract
Patients with malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. The responses to radiotherapy (RT) are mixed, and the biologic mechanisms underlying this heterogeneity in the radiation response of MPNSTs are not understood. Here, we combined bulk and single-cell transcriptomics, genome-wide CRISPR interference screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and patients’ samples to understand the mediators of the radiation response. Our data revealed that MPNSTs, but not benign plexiform neurofibromas, induced a type I IFN signature that functionally mediated the radiation response. Moreover, irradiation of immunocompetent mouse MPNST allografts led to IFN-mediated T cell recruitment and activation. Both host mouse T cells and intact tumor IFN receptor signaling were required for RT’s efficacy in mouse MPNST allografts. Analysis of human MPNST resection specimens demonstrated that increased microenvironmental and CD8+ T cell infiltration were associated with improved local control following RT. These results provide a preclinical rationale for combining immunomodulatory agents targeting IFN signaling to improve radiation responses in MPNSTs and potentially other soft tissue sarcomas.
Authors
Iowis Zhu, Julian Chien, Gabriel E. Rech, Kanish Mirchia, Sixuan Pan, Kaeli Miller, Joanna Pak, Rosanna Wustrack, Varun Monga, Steve E. Braunstein, Mark D. Adams, Line Jacques, Melike Pekmezci, S. John Liu, Harish N. Vasudevan
Abstract
Liver invasion is one of the most frequent events in the progression of gallbladder cancer (GBC). However, the cellular and pathological role of the tumor-liver–interface microenvironment in liver invasion is still enigmatic. Here, we applied single-cell and spatial transcriptomics to systematically investigate the cellular component and gene expression regulation of the microenvironment from the tumor to the liver, specifically the invasive boundary. Our analyses revealed that CXCL9+ macrophage–rich immune cell niches were accumulated in the tumor-liver invasive margin, where 2 subclasses of the CXCL9+ immune cell niches, CXCL9+TRAC+ (CT) and CXCL9+C1QB+ (CC) niches, were identified. CD8+ T cells were recruited by CXCL9+ macrophages through CXCL9-CXCR3 interaction in the CT niche, which was located adjacent to the liver. Moreover, the CC niche was proximal to the tumor core, where tumor cells induced CD8+ T cell exhaustion via LGALS4 expression. In addition, our cohort study showed that high CXCL9 and low LGALS4 in the liver invasion margin demonstrated a favorable prognosis and better responses to anti–PD-1 immunotherapy for patients with gallbladder cancer. Altogether, these findings demonstrate novel cellular and molecular mechanisms underlying liver invasion and offer clinical value for immunotherapies.
Authors
Maolan Li, Zhaonan Liu, Shenbing Shan, Ziyao Jia, Yongsheng Li, Fatao Liu, Lina Lu, Shimei Qiu, Chen Li, Ziyi Wang, Siyuan Yan, Yuhao Zhao, Lili Gao, Zhiqing Yuan, Yuanding Liu, Jiyao Ma, Jiayi Feng, Pengxiao Geng, Yiming Li, Xiaojing Xu, Xinhua Lin, Changjun Liu, Zebing Liu, Wenguang Wu, Xiangsong Wu, Wei Gong, Yanjing Li, Dongxi Xiang, Yongning He, Yun Liu, Rong Shao, Kwan Man, Wu Wei, Yingbin Liu
Abstract
The multi-omics data represented by genomic data from patients with metastatic triple-negative breast cancer (TNBC) is crucial for precision treatment, yet data on genomic alterations in metastatic cohorts and Chinese populations remains limited. We performed targeted sequencing of 296 metastatic TNBC samples from 296 patients treated at Fudan University Shanghai Cancer Center (October 2018 to November 2020) using a 484-gene panel, identifying 796 metastatic events across 18 organ sites. We characterized the genomic landscape of TNBC metastases and identified marked enrichment of polycystin-1 (PKD1) mutations in metastatic lesions — a finding validated in an independent paired primary metastasis cohort (n = 105). Notably, PKD1 mutations were associated with resistance to anti–PD-1 therapy, as validated across 3 clinical trials (NCT03805399, NCT04129996, and NCT04395989). Multi-omics analyses, combined with functional in vitro and in vivo mechanistic studies, revealed that PKD1 modulated the “desert” tumor immune microenvironment via C-C motif chemokine ligand 2 (CCL2), and targeting CCL2 could reverse immunotherapy resistance. This comprehensive genomic characterization of metastases enhances our understanding of tumor evolution, identifies PKD1 as a previously uncharacterized regulator of immune evasion to our knowledge, and suggests a potential therapeutic strategy to overcome immunotherapy resistance.
Authors
Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang
Abstract
Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes—pro-inflammatory and pro-resolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas pro-resolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After immuno-chemotherapy, mesenchymal-like tumors expanded pro-resolution macrophages through phagocytosis/efferocytosis, ω-3 fatty-acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T-cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via ω-6 fatty-acid pathways. Knocking down ELOVL5—an elongase involved in ω-3 and ω-6 metabolism—mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.
Authors
Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L. Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D. Lee, Xuan Li, Xiang Chen, David G. Edwards, Xiang H.-F. Zhang
Abstract
Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect was maintained in Sting–/– CT-2A cells, highlighting the direct role of the immune system in mediating the survival benefit. Single-cell RNA-Seq identified increased nitric oxide synthase 2 (Nos2) in inflammatory tumor-associated macrophages; however, the therapeutic effect was maintained in Nos2–/– mice. Additionally, 8803 reprogrammed the blood-brain barrier (BBB) by altering the Pecam and Cd147 pathways in endothelial cells; intracranial injection of 8803 induced bihemispheric BBB opening for up to 24 hours. Sting activation was visualized longitudinally using 3’-deoxy-3’-[18F]-fluorothymidine ([18F]-FLT) PET, which peaked 72–96 hours after 8803 administration. In summary, 8803 combined with RT triggers distinctive antiglioma immune reactivity, facilitates BBB opening, and warrants consideration for up-front clinical trials in glioblastoma, where treatment effects can be monitored using [18F]-FLT PET imaging.
Authors
Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen McCortney, Karl J. Habashy, Peng Zhang, Craig M. Horbinski, Lara Leoni, Ryan J. Avery, Rimas V. Lukas, Timothy L. Sita, David R. Raleigh, Sean Sachdev, Roger Stupp, Maciej S. Lesniak, David M. Ashley, Daniele Procissi, Michael A. Curran, Irina Balyasnikova, Amy B. Heimberger
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)