bims-tuinly 2026-04-26 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–04–26
24 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

A modular deep learning pipeline for stromal TILs scoring in breast cancer H&E slides.
Relevance of tumour-infiltrating lymphocytes (TILs) in oral mucosal melanoma: a systematic review.
Tumor-infiltrating lymphocyte therapy in metastatic vulvar melanoma: A case report and review of the literature.
Hierarchical Tissue-Specific Modeling of Pathology Images Predicts Response in HER2+ Breast Cancer.
Tumor Infiltrating Lymphocyte Therapy Combined With PD-1/LAG-3 Inhibition in Patients With Recurrent Platinum-Resistant Ovarian Cancer.
Associations between diffusion-weighted imaging and immunohistochemical features in hepatocellular carcinoma: a preliminary analysis of tumor-infiltrating lymphocytes and microvessel density expression.
Rationale and Design of the Cancer Immunotherapy Evidence Living (CIEL) Library: A Continuously Updated Clinical Trial Database of Cancer Immunotherapies.
Durvalumab in Combination With Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: Long-Term Analysis From the GeparNuevo Trial.
Level of estrogen receptor expression, histological grade, and computationally assessed stromal TILs on pre-treatment biopsies predict pathological complete response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer.
Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging.
CD28-driven ex vivo generation of stem-like memory CD8+ T cells bypassing CD3/TCR signaling.
Reprogramming Antitumor Immunity: NK Cell Strategies to Navigate the Immunosuppressive Tumor Microenvironment.
A novel photosensitizer-based photodynamic therapy reprograms the Kynurenine-AhR axis to boost antitumor immunity in breast cancer.
Protocol for metabolic profiling of antigen-specific CD8+ T cells using spectral flow cytometry.
GZMK expression within activated intratumoral T-cell subsets reflects differentiation efficiency and predicts response to cancer immunotherapy.
Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
Including tumor-infiltrating lymphocytes into the PREDICT prognostic model for triple-negative breast cancer survival.
Focusing on the Advances and Challenges of HER2-Targeted Therapy: Cutting-Edge Breakthroughs in Neoadjuvant Treatment for HER2-Positive Breast Cancer.
A responder-informed gut microbial consortium enhances anti-PD-1 efficacy in a mouse cancer model.
G2E3 Suppresses the Tumor-Killing Function of CD8+ T Cells in Hepatocellular Carcinoma by Boosting CLCN2 Ubiquitination.
Analysis of ovarian cancer immune cell profile identifies immunosuppressive states associated with adverse clinical attributes and survival times.
Targeting IRF1-TRIM21 axis enhances anti-tumor immunity by promoting ubiquitin-mediated degradation of FGL1 in non-small cell lung cancer.
Spleen-targeted neoantigen mRNA vaccine induces ISG15+ CD8+ T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma.
Checkpoint blockade and the stem-like T cell trade-off.

Comput Methods Programs Biomed. 2026 Apr 18. pii: S0169-2607(26)00139-2. [Epub ahead of print]282 109374

A modular deep learning pipeline for stromal TILs scoring in breast cancer H&E slides.

Shrief Abdelazeez, Faisal Ahmed, Laia Adalid, Krzysztof Siemion, Carlos Lopez, Marylene Lejeune, Hatem Rashwan, Anna Korzynska.

   BACKGROUND AND OBJECTIVE: Tumor-infiltrating lymphocytes (TILs) are an important indicator of immune activity in breast cancer, yet scoring them consistently on H&E slides remains challenging in routine pathology. This work presents a modular deep learning pipeline that delivers fully automated and continuous stromal TILs (sTILs) scores in line with the International Immuno-Oncology Biomarker Working Group (IIOBWG) guidelines.
METHODS: The pipeline combines three components: a TIL segmentation model refined through pathologist-guided active learning, a robust stroma segmentation network based on an enhanced DeepLabV3+, and a lightweight regression module that learns how TILs distribute within stromal regions. A new adaptive aggregation strategy integrates patch-level predictions into a single, clinically meaningful score while accounting for heterogeneous infiltration.
RESULTS: The system was evaluated on two independent datasets (60 and 112 WSIs) with expert-annotated ROIs, achieving strong agreement with pathologists (Pearson of 0.814; ICC of 0.808).
CONCLUSIONS: Importantly, the pipeline is interpretable: each stage produces human-readable outputs (stroma masks, TIL-in-stroma maps), and SegGradCAM visualizations confirm that predictions rely on biologically relevant tissue regions. These findings demonstrate the pipeline's potential as a reliable and clinically adaptable tool for standardized, fully automated TILs quantification in breast cancer pathology. The source code and pretrained models are publicly available at https://github.com/Shrief-Abdelazeez/TILs-Scoring.

Keywords:  Breast cancer; Convolutional neural networks; Deep learning; Digital pathology; H&E stained images; Quantitative pathology; TILs scoring; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.cmpb.2026.109374
Int J Oral Maxillofac Surg. 2026 Apr 22. pii: S0901-5027(26)00148-7. [Epub ahead of print]

Relevance of tumour-infiltrating lymphocytes (TILs) in oral mucosal melanoma: a systematic review.

C F J Bakhuis, E J de Ruiter, R de Bree, G E Breimer, E M Van Cann.

  Oral mucosal melanoma (OMM) is a rare and aggressive malignancy with a generally poor prognosis. Reliable prognostic markers for OMM are scarce, complicating disease management and patient counselling. Tumour-infiltrating lymphocytes (TILs) have shown prognostic value in other cancers, but their potential as a biomarker in OMM is not yet well defined. Hence, a systematic literature review, following the PRISMA guidelines, was conducted. The PubMed and Embase databases were searched for studies reporting on TILs in five or more OMM patients. Two studies reporting 102 OMM patients met the inclusion criteria and were included. Despite differences in TIL assessment methods and cut-offs, approximately 25% of OMM patients had demonstrable TILs. High TIL levels were associated with improved overall survival, although this reached statistical significance in only one study, describing 20 patients. In one study, low TIL levels were significantly associated with an increased risk of distant metastasis. Overall, despite the limited number of included studies, the findings suggest that TILs may serve as a prognostic marker in OMM, with higher TIL levels indicating more favourable outcomes. Larger, standardized studies are needed to validate these preliminary observations, refine TIL assessment methodologies and cut-off values, and to explore interactions with other prognostic markers. Ultimately, integrating the evaluation of TILs into OMM prognostic models could enhance patient stratification, guide treatment planning, and improve patient counselling.

Keywords:  Melanoma; Mouth neoplasms; Oral mucosa; Prognosis; Tumor biomarkers; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.ijom.2026.04.006
Gynecol Oncol Rep. 2026 Jun;65 102085

Tumor-infiltrating lymphocyte therapy in metastatic vulvar melanoma: A case report and review of the literature.

Aya Bashi, Riddhishkumar Shah, Jay S Lee, Georgia M Beasley, April K Salama, Haley A Moss.

   BACKGROUND: Vulvar melanoma is a rare and aggressive malignancy comprising less than 1% of all melanomas in women. Despite advances in immune checkpoint blockade, durable responses remain limited, and treatment of refractory disease poses a major challenge. Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a promising option for patients with metastatic mucosal melanoma resistant to standard immunotherapy.
CASE: We report a 48-year-old woman diagnosed with multifocal, unresectable vulvar melanoma who initially received ipilimumab and nivolumab, but discontinued due to immune-related colitis and progression of disease. She subsequently developed pulmonary, hepatic, and nodal metastases and underwent palliative vulvectomy for symptomatic relief. Following left inguinal lymph node harvest and autologous TIL expansion, she received lymphodepleting chemotherapy, TIL (lifileucel) infusion, and adjuvant interleukin-2 therapy. Her treatment course was notable for transient transaminitis, rash, and reversible encephalopathy. Follow-up PET-CT demonstrated a partial metabolic response with resolution of hepatic lesions and decreased pulmonary nodularity.
CONCLUSION: This case highlights the potential clinical benefit of TIL therapy in metastatic vulvar melanoma following checkpoint inhibitor failure, supporting its consideration as an emerging therapeutic option in this rare gynecologic malignancy.

Keywords:  Case report; Tumor-infiltrating lymphocyte therapy; Vulvar melanoma

DOI:  https://doi.org/10.1016/j.gore.2026.102085
Cyborg Bionic Syst. 2026 ;7 0554

Hierarchical Tissue-Specific Modeling of Pathology Images Predicts Response in HER2+ Breast Cancer.

Wensheng Cui, Tao Tan, Ming Fan, Lihua Li.

The structural and spatial heterogeneity of the tumor microenvironment in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (HER2+BC) poses major challenges for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. While immune-related biomarkers from whole-slide images have been widely explored, tissue-level interaction patterns and semantic features remain underexplored, particularly in characterizing structural organization within tissue compartments. To address this, we propose an interpretable hierarchical framework that models the tissue-specific organization of graph-based structural features and deep-learning-derived pCR scores (DLPSs) and integrates clinical variables to enhance pCR prediction. Whole-slide images were segmented into 5 biologically distinct compartments: tumor, stroma, stromal tumor-infiltrating lymphocytes (sTILs), intratumoral tumor-infiltrating lymphocytes (iTILs), and combined tumor-infiltrating lymphocytes (sTILs plus iTILs). Each compartment was modeled as a graph in which tile-level cluster centers served as nodes and their connections as edges. Structural features were computed using social network analysis (SNA) metrics to characterize spatial organization in each tissue compartment. In parallel, DLPSs were generated using a pretrained clustering-constrained multiple-instance learning model as a feature extractor, followed by training tissue-specific multilayer perceptron classifiers. The tissue-specific SNA features, DLPSs, and clinical variables were integrated for prediction. The model was trained on the Yale Response dataset and externally validated using the IMage-based Pathological REgistration and Segmentation Statistics (IMPRESS) HER2+ dataset. Across compartments, stroma achieved the highest predictive performance (area under the receiver operating characteristic curve [AUC] = 0.907), surpassing a reported method by 9.5%. Notably, SNA features achieved an AUC of 0.793, outperforming DLPS (0.596) and clinical variables (0.757). These findings suggest the value of integrating tissue-specific structural and semantic features for interpretable modeling of treatment response variability in HER2+BC.

DOI: https://doi.org/10.34133/cbsystems.0554
Int J Cancer. 2026 Apr 23.

Tumor Infiltrating Lymphocyte Therapy Combined With PD-1/LAG-3 Inhibition in Patients With Recurrent Platinum-Resistant Ovarian Cancer.

Tine J Monberg, Cathrine L Lorentzen, Marie C W Westergaard, Trine Z Iversen, Troels H Borch, Marco Donia, Sigrid M Mannering, Stine E W Banke, Özcan Met, Inge Marie Svane.

  Patients with ovarian cancer (OC) have not yet benefitted from the advances in immuno-oncology. While tumor infiltrating lymphocytes (TILs) can be expanded from OC tumors, previous trials have not demonstrated lasting responses. High expression of the immune checkpoints PD-1 and LAG-3 on TILs from OC provide a rationale for the addition of immune checkpoint inhibitors (ICI) to the treatment. In this clinical pilot study (NCT04611126), five patients with platinum-resistant recurrent OC were treated with TIL therapy and up to four cycles of combined treatment with PD-1-/LAG-3-inhibitors. The primary endpoint was safety and feasibility, while secondary endpoints included immune monitoring and clinical efficacy. Included patients had undifferentiated carcinoma (n = 1), high-grade serous OC (HGSOC) (n = 2) and low-grade serous OC (LGSOC) (n = 2). The treatment was safe and feasible with expected treatment-related toxicity; however, there was a relatively high rate of non-treatment-related complications. A decrease in tumor burden was observed in 80% (4/5) of patients, including two unconfirmed partial responses. In one patient, the response was supported by in vitro reactivity of the infused TILs toward autologous tumor cell line. Differences in baseline tumor burden, infusion product composition and responses were observed in LGSOC vs. HGSOC. Overall, this exploratory pilot study demonstrated a favorable safety profile and indications of clinical efficacy for TIL therapy combined with PD-1 and LAG-3 inhibition in platinum-resistant OC. Due to the low patient number, the results should be interpreted as hypothesis-generating, providing a rationale for conducting larger trials that carefully consider treatment timing and tumor histology.

Keywords:  immune checkpoint inhibitors; lymphocyte activating gene 3; ovarian cancer; tumor infiltrating lymphocyte therapy

DOI:  https://doi.org/10.1002/ijc.70510
Clin Exp Hepatol. 2025 Dec;11(4): 352-359

Associations between diffusion-weighted imaging and immunohistochemical features in hepatocellular carcinoma: a preliminary analysis of tumor-infiltrating lymphocytes and microvessel density expression.

Daniele Romeo, Theresa Richter, Anne-Kathrin Höhn, Hans-Michael Tautenhahn, Daniel Seehofer, Uwe Scheuermann, Timm Denecke, Hans-Jonas Meyer.

   Introduction: Imaging modalities can predict histopathological characteristics of tumors such as cellularity and proliferation potential, which has also been shown for hepatocellular carcinoma (HCC). Diffusion-weighted imaging can reflect cellularity of tumors and provide apparent diffusion coefficient (ADC) values as a quantitative imaging marker. This analysis elucidates possible associations between ADC values and several immunohistochemical features of HCC.
Material and methods: A cohort of 25 patients (4 female; 16%) with a mean age of 63 ±8.9 years met the inclusion criteria of this analysis. The main inclusion criteria were the availability of an MRI pre-interventional examination within 9 months before surgery and the availability of the histopathologic analysis. Immunohistochemical features included programmed cell death-ligand 1 (PD-L1) scores (immune cell score [ICS], tumor proportion score [TPS], and combined positive score [CPS]), glypican-3, tumor-infiltrating lymphocytes (TIL), stroma infiltrating lymphocytes (SIL), CD68 positive cells and microvessel density (MVD). ADC values were measured as ADCmax, ADCmean, and ADCmin.
Results: CD3+ TIL showed a moderate inverse correlation with ADCmax (r = -0.50, p = 0.01), ADCmean (r = -0.52, p = 0.008). CD34+ MVD showed higher expression in the group that showed diffusion restriction (mean 40 ±10.8 vs. 54 ±5.5, p = 0.0046). There was no correlation between ADC values and CD68+ positive cells, PDL-1, glypican-3 expression, or CD3+ SIL.
Conclusions: The present analysis demonstrated an inverse correlation between CD3-positive tumor-infiltrating lymphocytes and ADCmean and ADCmax. Diffusion restriction is correlated with increased microvessel density in HCC. ADC values could help to better characterize the tumor microenvironment of HCC in a non-invasive manner.

Keywords:  DWI; HCC; diffusion restriction; tumor microenvironment

DOI:  https://doi.org/10.5114/ceh.2025.155477
Health Sci Rep. 2026 Apr;9(4): e72221

Rationale and Design of the Cancer Immunotherapy Evidence Living (CIEL) Library: A Continuously Updated Clinical Trial Database of Cancer Immunotherapies.

Kim Boesen, Julian Hirt, Pascal Düblin, Heinz Läubli, Benjamin Kassenda, Lars G Hemkens, Perrine Janiaud.

   Background and Aims: Immunotherapies for cancers are tested in large numbers of clinical trials. It is difficult for clinicians and researchers to stay current with the evidence, and traditional systematic reviews and clinical guidelines are not suited to ensure a continued overview of all trials and their results. To address this problem, we designed the Cancer Immunotherapy Evidence Living (CIEL) Library.
Methods: We included planned, ongoing, and completed interventional trials of immunotherapies for cancer, regardless of trial design (e.g., randomization, blinding, and type of comparator). We systematically searched PubMed (for published reports) and ClinicalTrials.gov (for registered clinical trials). PubMed-retrieved records were screened using the AI-assisted software ASReview and manually extracted and curated. We imported data from ClinicalTrials.gov using the Clinical Trials Transformation Initiative database, which then requires further curation. The CIEL-Library was implemented as a web application. It also contained the "Match My Patient" feature, a patient-centered clinical decision support system, aiming to filter planned, ongoing, or completed trials based on four patient characteristics (disease staging, previous treatments, performance status, and location). We piloted our database with one type of cancer immunotherapy, the tumor-infiltrating lymphocytes (TIL) transfer. The CIEL-Library was a prototype and no further developments are planned.
Conclusions: The CIEL-Library offers a blueprint for a dynamic evidence synthesis infrastructure by providing a collection of clinical trials with curated trial characteristics and results. This blueprint may be applied across fields, specialties, and topics. The main challenges to making a database of clinical trials are the time and resources needed to populate it with curated and updated data. The CIEL-Library project highlights the potential and the main limitations of designing trial databases intended to be used in routine care.

Keywords:  cancer; databases; immunotherapy; systematic reviews

DOI:  https://doi.org/10.1002/hsr2.72221
J Clin Oncol. 2026 Apr 20. JCO2502311

Durvalumab in Combination With Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: Long-Term Analysis From the GeparNuevo Trial.

Sibylle Loibl, Michael Untch, Jens Huober, Vanessa Schaser, Michael Braun, Carsten Denkert, Andreas Hartkopf, Jens-Uwe Blohmer, Claus Hanusch, Theresa Link, Mattea Reinisch, Dirk-Michael Zahm, Rudolf Weide, Vesna Bjelic-Radisic, Peter Staib, Hans Tesch, Kerstin Rhiem, Ralf Lorenz, Julia Rey, Andreas Schneeweiss.

The phase II GeparNuevo trial investigated whether adding durvalumab to neoadjuvant chemotherapy (NACT) only in patients with early triple-negative breast cancer cT1b-cT4a-d would improve pathologic complete response (pCR) rate and patient survival. Hundred and seventy-four patients were randomly assigned to receive durvalumab or placebo concurrently with nab-paclitaxel once per week and followed by dose-dense epirubicin and cyclophosphamide. With 86.4 months of median follow-up compared with the previously reported 43.7 months, durvalumab showed sustained significant improvements in long-term outcomes as defined by STEEP compared with placebo regarding not only invasive disease-free survival (iDFS; hazard ratio [HR], 0.56 [95% CI, 0.32 to 0.99]; stratified log-rank P = .0431), but also distant disease-free survival (DDFS; HR, 0.41 [95% CI, 0.21 to 0.80]; P = .0069) and overall survival (OS; HR, 0.33 [95% CI, 0.14 to 0.79]; P = .0085). All analyses were stratified by stromal tumor-infiltrating lymphocytes (sTILs) at baseline (low [≤10%], intermediate [11%-59%], high [≥60%]). In exploratory subgroup analysis, patients with nodal involvement at baseline demonstrated a greater iDFS benefit (HR, 0.33 [95% CI, 0.144 to 0.771]; P = .01; Pinteraction = 0.045). sTILs in residual disease (RD) could be assessed in 39/71 patients without pCR. Post hoc analyses by sTILs high (>10%) versus low (≤10%) in RD showed estimated 7-year iDFS rates of 92.3% (95% CI, 56.6 to 98.9) and 51.4% (95% CI, 29.2 to 69.7), respectively. Hence, adding durvalumab to dose-dense NACT without adjuvant continuation of checkpoint inhibition improved long-term survival outcomes, irrespective of the extent of pathologic response. This underscores the necessity to re-evaluate the adjuvant continuation of checkpoint inhibition.

DOI: https://doi.org/10.1200/JCO-25-02311
Virchows Arch. 2026 Apr 20.

Level of estrogen receptor expression, histological grade, and computationally assessed stromal TILs on pre-treatment biopsies predict pathological complete response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer.

Dusan Rasic, Elisabeth Ida Specht Stovgaard, Anne Marie Bak Jylling, Truc Hoang, Thomas le Fevre, Roberto Salgado, Johan Hartman, Mattias Rantalainen, Anne-Vibeke Lænkholm.

  Estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) is the most common BC subtype. Patients with this subtype rarely achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NACT), and the population most likely to benefit remains unclear. This highlights the need to identify reliable markers of response, particularly in the context of emerging chemoimmunotherapy strategies. We retrospectively included 415 patients diagnosed with ER+/HER2- BC between 2016 and 2020 from three Danish pathology departments. We analysed associations between standard clinicopathological variables and computationally assessed stromal tumor-infiltrating lymphocytes (sTILs) with response rates and long-term outcomes. To define clinically useful cut-offs, we performed threshold analysis for ER-expression and sTIL levels. The pCR rate in the study population was 6.3%, while pCR/RCB-I was observed in 15.9% of all patients. Lower ER-expression, higher grade, and higher computational sTILs were associated with greater odds of achieving pCR and good response. Threshold analysis revealed optimal cut-off points of 60% for ER expression and 20% for sTILs. Patients with simultaneously high-grade, high sTILs, and ER < 60% were the most likely to achieve good response to NACT (pCR rate 44%, pCR/RCB-I rate 62%), while patients with low-grade, low sTILs, and high ER-expression achieved pCR in only 1% and pCR/RCB-I in 11% of cases. Response to NACT is strongly influenced by ER expression, tumor grade, and sTIL levels. Composite profiles combining these factors can help identify patients most likely to achieve meaningful response, while also highlighting subgroups with low benefit where alternative treatment strategies may be more appropriate.

Keywords:  ER-positive breast cancer; Neoadjuvant chemotherapy; Predictive biomarkers; Residual cancer burden

DOI:  https://doi.org/10.1007/s00428-026-04522-1
Cancer Sci. 2026 Apr 20.

Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging.

Koji Kitaoka, Shuhei Hirose, Yu Wang, Tomonori Yaguchi, Kenji Chamoto.

  Recent studies have demonstrated the intricate relationship between tumor immunity, aging, and inflammation. Mitochondrial activity is one of the major connection hubs of this physiological interplay. Fatty acid oxidation (FAO) is a center of the mitochondrial metabolic pathway and plays a pivotal role in maintaining cellular homeostasis. Dysfunction in mitochondrial FAO leads to an accumulation of reactive oxygen species (ROS), contributing to oxidative stress and chronic inflammation. This persistent inflammatory stress not only accelerates aging but also impairs immune surveillance, facilitating tumor progression. Modulation of mitochondrial FAO reprograms the metabolism of tumor-infiltrating lymphocytes and macrophages, thereby impacting anti-tumor immunity. Understanding these interconnected pathways offers potential therapeutic avenues to enhance cancer immunotherapy and mitigate inflammation.

Keywords:  T cell exhaustion; T cell senescence; glycolysis; mitochondrial morphology; oxidative stress

DOI:  https://doi.org/10.1111/cas.70388
Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2524626123

CD28-driven ex vivo generation of stem-like memory CD8+ T cells bypassing CD3/TCR signaling.

Fumie Ihara, Yota Ohashi, Evey Y F Zheng, Saori Fukao, Rowena Rodrigo, Babak Noamani, Giselle M Boukhaled, Ben X Wang, Dong-Hoon Han, Xinyu Wei, Brian D Burt, Kayoko Saso, Yukiko Matsunaga, Dalam Ly, Yuki Kagoya, Marcus O Butler, Tak W Mak, Samuel D Saibil, Naoto Hirano.

  Adoptive T cell therapies typically rely on ex vivo CD3/CD28 stimulation, which promotes effector differentiation and limits the persistence of transferred cells. Stem cell-like memory T cells (Tscm), with their capacity for self-renewal and multipotency, represent an ideal therapeutic subset but remain difficult to generate at scale. Here, we present a CD3-independent strategy using artificial antigen-presenting cells expressing a membrane-bound CD28 superagonist (αCD28-aAPCs) to expand CD8+ T cells with Tscm-like features. In naïve CD8+ T cells, αCD28-aAPC stimulation initiates a distinct transcriptional and epigenetic program, marked by high TCF1 expression, metabolic fitness, and resistance to exhaustion-key hallmarks of the Tscm phenotype. Mechanistically, this approach circumvents canonical CD3/TCR signaling and notably avoids induction of IRF4, a key transcription factor that drives BLIMP1 upregulation, TCF1 downregulation, and glycolytic commitment during effector differentiation. Instead, sustained CD28 signaling alone reprograms T cells toward a Tscm-like state. Upon subsequent antigen encounter and CD3 engagement, these αCD28-aAPC-expanded T cells mount robust effector responses while retaining superior persistence and antitumor activity in preclinical models. Our findings reveal an underappreciated role of CD28 signaling in guiding Tscm-like fate through IRF4 suppression and establish a platform for generating durable and functionally potent T cell therapies.

Keywords:  CD28 signaling; CD3-independent activation; adoptive T cell therapy; artificial antigen-presenting cells; stem cell–like memory T cells

DOI:  https://doi.org/10.1073/pnas.2524626123
Adv Sci (Weinh). 2026 Apr 21. e75326

Reprogramming Antitumor Immunity: NK Cell Strategies to Navigate the Immunosuppressive Tumor Microenvironment.

Tereza Kochs, Pranay Nath, Alice Chen, Rizwan Romee, Andreia Maia.

  Tumor immune escape is a major barrier to durable cancer immunotherapy, as advanced malignancies create a tumor microenvironment (TME) that preferentially exhausts and disables T cell responses. While most approved cell therapies are T cell-based, this limitation motivates the exploration of an alternative effector cell platform. Natural killer (NK) cells, innate cytotoxic lymphocytes capable of antigen-independent recognition and killing, offer a compelling foundation for next-generation therapies with an improved safety profile. In this review, we first outline the cellular, molecular, and metabolic features of the immunosuppressive TME that restrict cytotoxic lymphocyte function, emphasizing mechanisms that limit immune cell-mediated responses. We then summarize key aspects of NK cell biology that can circumvent these barriers and critically evaluate current NK-based strategies, including engineered chimeric antigen receptor (CAR)-NK products and metabolic and trafficking interventions. Finally, we highlight emerging in vivo viral and mRNA/lipid nanoparticle platforms for CAR-NK generation and their potential to enhance scalability and therapeutic durability.

Keywords:  CAR‐NK cells; cell therapy; immunotherapy; in vivo gene editing; natural killer cells; tumor immune escape

DOI:  https://doi.org/10.1002/advs.75326
Redox Biol. 2026 Apr 15. pii: S2213-2317(26)00169-2. [Epub ahead of print]93 104171

A novel photosensitizer-based photodynamic therapy reprograms the Kynurenine-AhR axis to boost antitumor immunity in breast cancer.

Yuetong Liu, Ge Hong, Tianjun Liu, Hong Liu.

  Photodynamic therapy (PDT) has emerged as a promising local treatment for breast cancer, with emerging evidence highlighting its potential to modulate the immune response. However, its effects on tumor microenvironment (TME) metabolism remain poorly understood. In this study, we introduce a novel photosensitizer, DTP, which efficiently generates reactive oxygen species and induces apoptosis in breast cancer cells in vitro. In vivo, DTP preferentially accumulates in tumors, significantly inhibiting tumor growth and reducing Ki-67 expression upon 650 nm irradiation. Untargeted metabolomics revealed significant alterations in the tryptophan metabolism pathway following DTP-PDT. Further targeted metabolomic analysis identified a specific reduction in kynurenine (Kyn), an immunosuppressive metabolite, within the tumor. Mechanistically, DTP-PDT reduced indoleamine 2,3-dioxygenase 1 (IDO1)-dependent Kyn production, diminished AhR nuclear localization and decreased AhR transcriptional activity in tumor-infiltrating T cells. This metabolic reprogramming alleviated the immunosuppressive TME, as evidenced by increased infiltration of CD8+ T cells and a reduction in regulatory T cells. Notably, exogenous Kyn partially restored the Kyn-AhR axis and attenuated the immune remodeling induced by DTP-PDT. Building on these immune-activating effects, we combined DTP-PDT with PD-L1 blockade, which significantly suppressed pulmonary metastasis and enhanced central memory T-cell generation, resulting in durable systemic antitumor immunity.

Keywords:  Breast cancer; Indoleamine 2,3-dioxygenase 1; Kynurenine-AhR axis; PD-L1 blockade; Photodynamic therapy; Tumor immunometabolism

DOI:  https://doi.org/10.1016/j.redox.2026.104171
STAR Protoc. 2026 Apr 22. pii: S2666-1667(26)00170-X. [Epub ahead of print]7(2): 104517

Protocol for metabolic profiling of antigen-specific CD8+ T cells using spectral flow cytometry.

J Fréderique de Graaf, Nils Mülling, Ramon Arens.

  CD8+ T cells rely on tightly regulated metabolic remodeling to support effector function. Here, we present a protocol for single-cell metabolic profiling of rare antigen-specific CD8+ T cells in unstimulated and antigen-stimulated conditions using spectral flow cytometry. The workflow enables detailed assessment of key metabolic pathways, including glycolysis, fatty acid oxidation, amino acid metabolism, the pentose phosphate pathway, and mitochondrial oxidative phosphorylation. For complete details on the use and execution of this protocol, please refer to Mülling et al.1.

Keywords:  Cell Biology; Immunology; Metabolism

DOI:  https://doi.org/10.1016/j.xpro.2026.104517
NPJ Precis Oncol. 2026 Apr 18.

GZMK expression within activated intratumoral T-cell subsets reflects differentiation efficiency and predicts response to cancer immunotherapy.

Cem M Sievers, Tian-Gen Chang, Yvette Robbins, Jay Friedman, Marco Craveiro, Xinping Yang, Christopher Silvin, Jason M Redman, Patrick Soon-Shiong, Wiem Lassoued, Martha Quezado, Wojciech Mydlarz, Nancy P Judd, Jeffrey Schlom, James Gulley, Eytan Ruppin, Clint T Allen.

Neoadjuvant immunotherapies (NITs) have demonstrated clinical benefit in head and neck carcinoma and other cancers by enhancing T cell-mediated anti-tumor immunity. However, disease recurrence remains a major challenge in a significant proportion of patients. Characterization of T cell dynamics underlying NIT outcomes may lead to improved treatment strategies. Here, we identify baseline intratumoral T cell differentiation efficiency as a predictor of response to NIT. Clonal analysis of tumor-emergent T cells post-treatment revealed granzyme K (GZMK) expression within differentiated subsets as a marker of recent differentiation. Efficient pre-treatment differentiation of GZMK+ progenitor T cells toward activated effectors predicts increased treatment-induced tumor regression. Consistently, pre-treatment tumor-infiltrating T cell clones predominantly adopt either exhausted, tissue-resident memory-like, or peripherally enriched GZMK+ progenitor states, implicating impaired intratumoral differentiation in limited anti-tumor immunity at baseline. Together, our findings demonstrate that GZMK+ T cell profiles reflect baseline anti-tumor immunocompetence and offer a clinically actionable biomarker for predicting immunotherapy response. NCT04247282, ClinicalTrails.gov, registered 1/30/2020 and NCT03429036, ClinicalTrails.gov, registered 11/06/2020.

DOI: https://doi.org/10.1038/s41698-026-01437-7
Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00244-9. [Epub ahead of print]333 124220

Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.

Yang Liu, Xu Zhou, Weilin Li, Bing Feng, Jingshan Sun, Ruzhen Li, Huixia Ma, Lanpeng Li, Feng Zhou, Jianxun Ding, Xuesi Chen.

  Immunotherapy efficacy is constrained by immunosuppressive features of the tumor microenvironment (TME) beyond canonical molecular checkpoints, including emerging extracellular ionic regulatory mechanisms that remain poorly characterized. Here, we identify potassium ion (K+) as a metabolically coupled ionic immune checkpoint that suppresses CD8+ T cell antitumor immunity. Using a murine melanoma model with an elevated-K+ microenvironment, we demonstrate that excess extracellular K+ profoundly impairs CD8+ T cell proliferation, activation, and effector function while promoting functional exhaustion without reducing T cell abundance. Mechanistically, K+-mediated immunosuppression is accompanied by restricted glucose uptake, suppressed glycolytic flux, and impaired mitochondrial fitness, establishing metabolic insufficiency as a key basis for ionic checkpoint-driven T cell dysfunction. To therapeutically target this extracellular and non-molecular suppressive mechanism, we develop a localized K+-depleting strategy by encapsulating the clinically approved potassium-binding agent sodium zirconium cyclosilicate (ZS-9) within a thermosensitive poly (lactide-co-glycolide)-polyethylene glycol-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel, forming a peritumoral K+-scavenging depot. This biomaterial platform efficiently remodels the ionic TME, restores CD8+ T cell metabolic fitness and effector function, alleviates T cell exhaustion, and significantly enhances the antitumor efficacy of adoptive cell therapy (ACT). Collectively, this work establishes extracellular ionic modulation as a metabolically grounded immune checkpoint mechanism and highlights biomaterials-based ionic remodeling as a translatable strategy to augment cancer immunotherapy.

Keywords:  Adoptive cell therapy; Immunomodulatory biomaterials; Ionic immune checkpoint; K(+)-scavenging hydrogel; T cell metabolism

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124220
Ann Oncol. 2026 Apr 21. pii: S0923-7534(26)00152-3. [Epub ahead of print]

Including tumor-infiltrating lymphocytes into the PREDICT prognostic model for triple-negative breast cancer survival.

International Immuno-Oncology Biomarker Working Group

   BACKGROUND: Stromal tumor infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple-negative breast cancer (TNBC) patients. We aimed to incorporate sTILs into the PREDICT model for women with early-stage TNBC to guide chemotherapy decisions.
PATIENTS AND METHODS: We included 3698 women with early-stage TNBC, diagnosed between 1979 and 2017, from two pooled cohorts with sTILs scored according to international guidelines to update PREDICT version 2.3. The updated model, PREDICT_sTILs, is a Cox regression model with sTILs and the PREDICT prognostic index as predictors, and breast cancer-specific survival as the outcome. Internal-external validation was conducted using leave-one-region-out cross-validation, with calibration assessed by the observed-to-expected (O/E) ratio and discrimination by area under the curve (AUC). We compared the clinical values of PREDICT_sTILs and PREDICT through decision curve analysis, examining net true high-risk and low-risk classifications across risk thresholds of 10-year breast cancer mortality above 8-15%.
RESULTS: Among the 3698 patients, 1806 received chemotherapy while 1892 were chemotherapy-naïve. Chemotherapy-treated patients had a median age of 50 years, tumor size of 25mm, and 1 positive lymph node (pN). The chemotherapy-naïve patients had a median age of 55 years, tumor size of 20mm, and 0 pN. Within 5 and 10 years, 741 and 860 deaths were attributed to breast cancer, respectively. PREDICT_sTILs showed strong internal-external validity, with comparable calibration and discrimination at both time points: pooled O/E ratios of 0.98 (95% CI: 0.69-1.41) at 5 years and 0.99 (95%CI: 0.72-1.35) at 10 years, and AUCs of 0.74 (95%CI: 0.72-0.77) and 0.74 (95%CI: 0.70-0.78), respectively. Compared to PREDICT, PREDICT_sTILs identified 19-60 additional net true low-risk patients, and 3-10 additional net true high-risk patients per 1000 chemotherapy-naïve patients at the risk thresholds of 8-15% at 10 years.
CONCLUSION: Adding sTILs to PREDICT improves its ability to inform chemotherapy decisions for early-stage TNBC patients, especially in identifying low-risk individuals who may safely forgo chemotherapy.

Keywords:  Chemotherapy-decision making; PREDICT; Prognostication; Triple-negative breast cancer; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.annonc.2026.04.011
Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261446455

Focusing on the Advances and Challenges of HER2-Targeted Therapy: Cutting-Edge Breakthroughs in Neoadjuvant Treatment for HER2-Positive Breast Cancer.

Anqi Shang, Yunjing Xiong, Min Li, Wanxin Tang, Keyu Wan, Zekang Deng, Xianxian Mao, Haizhu Chen.

  HER2-positive breast cancer, characterized by overexpression of the human epidermal growth factor receptor 2 (HER2), accounts for approximately 15-20% of all breast cancers and is associated with aggressive tumor behavior and poor prognosis. Advances in HER2-targeted therapies, such as monoclonal antibodies (trastuzumab, pertuzumab), tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs), have significantly improved treatment outcomes in this subtype. Neoadjuvant therapy, administered before surgery, has become a cornerstone in managing HER2-positive breast cancer by improving pathological complete response (pCR) rates and survival outcomes. This review provides a comprehensive analysis of recent advancements in HER2-targeted neoadjuvant therapies, highlighting the mechanisms of action, clinical efficacy, and synergistic effects when combined with chemotherapy. Key challenges, such as treatment-related toxicities, and the potential for personalized treatment strategies based on biomarkers like tumor-infiltrating lymphocytes (TILs) and HER2-enriched subtypes, are discussed. Future directions emphasize optimizing treatment regimens to enhance efficacy while minimizing adverse effects, with novel agents such as trastuzumab deruxtecan (T-DXd) showing promise for expanding the therapeutic landscape.

Keywords:  HER2-positive breast cancer; HER2-targeted therapies; antibody-drug conjugates (ADCs); monoclonal antibodies; neoadjuvant therapy; trastuzumab; tyrosine kinase inhibitors (TKIs)

DOI:  https://doi.org/10.1177/15330338261446455
Microbiome Res Rep. 2026 ;5(1): 2

A responder-informed gut microbial consortium enhances anti-PD-1 efficacy in a mouse cancer model.

Uk Jin Jeong, Mohammed Ali, Yun Jee Park, Jin Sun You, Sang Sun Yoon.

  Aim: Immune checkpoint inhibitors (ICIs), particularly anti-programmed cell death protein 1 (PD-1) therapy, have improved cancer treatment outcomes, yet durable benefit is achieved in only a subset of patients. Growing evidence implicates the gut microbiome as a modulator of ICI responsiveness, but defined and experimentally validated microbial strategies remain limited. This study aimed to identify responder-associated gut microbes and to evaluate a defined bacterial consortium for enhancing PD-1 blockade efficacy. Methods: Publicly available shotgun metagenomic datasets from anti-PD-1-treated cancer patients were re-analyzed to compare gut microbiome profiles between responders and non-responders. Bacterial taxa reproducibly enriched in responders were selected based on consistency across analytical criteria and cultivability and assembled into a four-strain consortium (UJ-04). The immune-adjuvant potential of UJ-04, alone or combined with anti-PD-1 therapy, was evaluated in a B16-F10 melanoma mouse model, with tumor growth and immune responses assessed by flow cytometry. Results: Metagenomic re-analysis identified four commensal bacterial taxa consistently enriched in responder patients, forming the defined UJ-04 consortium. While UJ-04 alone showed minimal antitumor activity, combination treatment with anti-PD-1 significantly enhanced tumor growth inhibition compared with anti-PD-1 monotherapy. This effect was accompanied by increased intratumoral CD8+ T cells and natural killer cells, with concordant immune trends in peripheral compartments. Conclusion: A responder-informed, defined microbial consortium functionally translates clinical microbiome associations into in vivo validation and enhances PD-1 blockade efficacy by modulating host antitumor immunity. These findings support defined bacterial consortia as microbiome-based immunomodulatory adjuncts for immunotherapy.

Keywords:  Gut microbiota; anti-PD-1; cancer immunotherapy; host-microbiome interactions; immune checkpoint inhibitors; tumor microenvironment

DOI:  https://doi.org/10.20517/mrr.2025.117
FASEB J. 2026 Apr 30. 40(8): e71719

G2E3 Suppresses the Tumor-Killing Function of CD8+ T Cells in Hepatocellular Carcinoma by Boosting CLCN2 Ubiquitination.

Fan Zhou, Ting Chen, Xingguo Tan, Jun Yu, Mengzhi Xiao, Jun Guo.

  In the pathogenesis of hepatocellular carcinoma (HCC), impaired CD8+ T cell function is a critical factor in immune evasion. Although CLCN2 has been implicated in immunomodulation, its role in regulating CD8+ T cell-mediated antitumor immunity in HCC remains unclear. The expression of G2E3 in HCC was analyzed using the TCGA database, qPCR, and western blot. The UbiBrowser database was employed to predict CLCN2 as a downstream substrate of G2E3. Protein interactions were validated via Co-IP and in vivo ubiquitination assays. IFN-γ, TNF-α, and Granzyme B levels were measured using ELISA kits, while CD44 and CD134 levels in CD8+ T cells were examined via flow cytometry. The cytotoxic activity of CD8+ T cells against HCC cells was evaluated using an LDH assay. An allograft mouse tumor model was utilized to determine whether the G2E3-CLCN2 axis drove HCC progression by suppressing T cell immunity. We herein discovered that G2E3 was highly expressed in HCC and positively linked with poor prognosis. Mechanistically, G2E3 functioned as an E3 ubiquitin ligase, mediating the ubiquitination and subsequent degradation of CLCN2. Rescue experiments revealed that CLCN2 enhanced the antitumor activity of CD8+ T cells, whereas G2E3 overexpression attenuated this effect. Furthermore, in an allograft mouse tumor model, activation of the G2E3-CLCN2 axis reduced CD8+ T cell infiltration and activity in tumors, thereby driving tumor growth. This investigation elucidates the molecular mechanism by which HCC suppresses CD8+ T cell function to facilitate immune escape, suggesting that targeting the G2E3-CLCN2 axis may represent a potential therapeutic strategy to enhance antitumor immunity.

Keywords:  CD8+ T cells; CLCN2; G2E3; hepatocellular carcinoma; ubiquitination

DOI:  https://doi.org/10.1096/fj.202503004RR
PLoS One. 2026 ;21(4): e0346746

Analysis of ovarian cancer immune cell profile identifies immunosuppressive states associated with adverse clinical attributes and survival times.

Ana Moscoso, Navid Mohammad Mirzaei, Leili Shahriyari.

The ovarian tumor microenvironment (TME) is highly immunosuppressive, limiting immunotherapy effectiveness. We investigated whether the composition, ratios, and polarization of infiltrating immune cells provide prognostic value in ovarian cancer (OC). Our analysis revealed that immune ratios, including CD8/Treg and CD8/CD4, were more predictive of survival than absolute CD8 + , CD4 + , or Treg levels. Prior studies have reported associations between higher CD8/Treg ratios and improved responses to immune checkpoint inhibitors, highlighting the importance of effector-regulator balance; however, immunotherapy response was not evaluated in this cohort. Additionally, macrophage polarization proved to be crucial: pro-tumor M2-macrophages were associated with vascular invasion, persistent tumor, and worse survival, while higher naïve M0-macrophage levels predicted improved outcomes. Surprisingly, anti-tumor M1-macrophages lacked prognostic significance, suggesting possible benefits in preserving an M0-macrophage pool. Neutrophil infiltration, though relatively uncommon, correlated with poor survival, supporting reports that neutrophils suppress T-cell responses. Immune infiltration was linked to aggressive features such as vascular invasion, reflecting both heightened recognition and compensatory recruitment of suppressive populations. Unsupervised clustering identified four immune-defined subtypes, with worse survival in clusters enriched for M2-macrophages and CD4 + T-cells and depleted in M0-macrophages, particularly in advanced disease. Overall, our findings highlight the prognostic value of immune ratios, macrophage polarization, and neutrophil activity in OC, suggesting new avenues for risk stratification and future therapeutic investigation.

DOI: https://doi.org/10.1371/journal.pone.0346746
Commun Biol. 2026 Apr 22.

Targeting IRF1-TRIM21 axis enhances anti-tumor immunity by promoting ubiquitin-mediated degradation of FGL1 in non-small cell lung cancer.

Yuchen Zhang, Pingjing Zhou, Yifan Guo, Hongyu Zhang, Guangyin Zhao, Jun Yin, Di Ge, Ronghua Liu, Jie Gu, Chunyi Zhang.

Immunotherapy has emerged as a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC), but over half of patients fail to benefit, largely due to tumor heterogeneity and a complex tumor microenvironment. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a recently identified immune checkpoint ligand, is targeted by tripartite motif-containing protein 21 (TRIM21) for proteasomal degradation, thereby enhancing the anti-tumor activity of cytotoxic T lymphocytes (CTLs). We further show that interferon regulatory factor 1 (IRF1) regulates TRIM21 transcription. Artemisinin upregulates the IRF1-TRIM21 axis, promoting FGL1 degradation. In high FGL1 expressed tumors, artemisinin in combination with anti-programmed cell death protein 1 (anti-PD-1) therapy enhances immunotherapeutic efficacy. Clinically, an elevated FGL1/TRIM21 protein ratio is associated with poor prognosis in NSCLC. Collectively, these findings elucidate a post-translational regulatory mechanism of FGL1 in tumor progression and support the development of a rational combination immunotherapy strategy for NSCLC treatment.

DOI: https://doi.org/10.1038/s42003-026-10070-w
Cell Rep Med. 2026 Apr 20. pii: S2666-3791(26)00171-0. [Epub ahead of print] 102754

Spleen-targeted neoantigen mRNA vaccine induces ISG15+ CD8+ T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma.

Xinyi Lin, Geng Chen, Ruijing Tang, Ming Wu, Da Zhang, Fangzhou Lin, Jianhua Guan, Jing Yang, Xiuqing Dong, Xiaoyuan Zheng, Liman Qiu, Haijun Yu, Zhixiong Cai, Xiaolong Liu.

  The efficacy of neoantigen vaccine for advanced hepatocellular carcinoma (HCC) is limited largely due to insufficient T cell mobilization and activation. Herein, we develop a spleen-targeted neoantigen mRNA vaccine (STNvac) with highly efficient spleen-selective mRNA transfection. Using a three-dose vaccination regimen, STNvac demonstrates remarkable therapeutic efficacy in orthotopic HCC model with a high likelihood of complete tumor regression and significantly improved survival rates (p < 0.0001). Notably, we identify a distinct ISG15+ CD8+ T cell population as crucial mediators of STNvac-induced immunity with potent antigen-processing and cytotoxic capacities. Intriguingly, STNvac promotes the formation of tertiary lymphoid structures (TLSs) through GZMA-F2R-mediated interactions between ISG15+ CD8+ T cells and antigen-presenting cells (APCs), which is also confirmed in HCC patients. Taken together, our findings demonstrate the potent antitumor efficacy of spleen-targeted mRNA vaccine and reveal its underlying immune cell interactive mechanisms, presenting high potential for clinical translation.

Keywords:  GZMA-F2R interaction; ISG15(+) CD8(+) T cells; neoantigen; spleen-targeted mRNA vaccine; tertiary lymphoid structure (TLS)

DOI:  https://doi.org/10.1016/j.xcrm.2026.102754
Mol Oncol. 2026 Apr 20.

Checkpoint blockade and the stem-like T cell trade-off.

Julie M Mazet, Johanna A Joyce.

  Stem-like T cells are central to the efficacy of programmed cell death protein 1 (PD1) blockade, sustaining long-term immune responses by serving as a renewable reservoir for anti-tumor effector CD8+ T cells. However, the mechanisms governing their maintenance and regulation in cancer remain incompletely understood. Addressing this gap, Hor et al. combined high-dimensional 3D-imaging with immunological profiling to define the niche of stem-like T cells within tumor-draining lymph nodes in murine cancer models. Their study identifies a critical role for conventional type 1 dendritic cells (cDC1s) and the PD1 pathway in preserving high-affinity tumor-specific stem-like T cells. cDC1s deliver sustained T-cell receptor (TCR) stimulation together with PD-L1/2 co-inhibitory signals that support stemness, proliferation, and survival. Strikingly, disruption of PD1 signaling transiently enhances effector T cell expansion but promotes differentiation and apoptosis of stem-like T cells, ultimately depleting this essential pool. These findings reveal a potential long-term vulnerability of immune checkpoint blockade, particularly when tumors are not eradicated during the initial treatment response.

Keywords:  Stem‐like T cells; cancer immunity; immune checkpoint blockade

DOI:  https://doi.org/10.1002/1878-0261.70257