Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Immune checkpoint inhibitor-related myocarditis in patients with thymic epithelial tumors: a retrospective cohort analysis.
Zeng H, Kang J, Pu S … +11 more , Dai C, Jiang J, Chen Y, Chen Y, Fu L, Liu H, Guo M, Yi H, Chen H, Zhong W, Xue Y
Cancer Immunol Immunother · 2026 Apr · PMID 41925910 · Full text
BACKGROUND: Immune checkpoint inhibitor-related myocarditis (ICI-M) is increasingly recognized, but real-world data in thymic epithelial tumors (TET) remain limited. OBJECTIVE: To evaluate the clinical outcomes, focusing...
BACKGROUND: Immune checkpoint inhibitor-related myocarditis (ICI-M) is increasingly recognized, but real-world data in thymic epithelial tumors (TET) remain limited. OBJECTIVE: To evaluate the clinical outcomes, focusing on ICI-M, in patients with TET receiving immune checkpoint inhibitors (ICI). METHODS: This retrospective study examined patients with TET at Guangdong Provincial People's Hospital in China from January 2018 to March 2024. We assessed the biomarker changes by comparing the baseline values to peak levels during ICI therapy. Clinical characteristics, disease progression, and outcomes of patients with ICI-M were also analyzed. To investigate the relationships between clinical factors or biomarkers and all-cause mortality, we performed univariable Cox regression analysis. RESULTS: Among 31 patients, 7 developed ICI-M, all in the thymoma subgroup (7/12, 58.3%). During a median follow-up of 494 days (262-858), 13 patients died (13/31, 41.9%), including 6 cardiovascular deaths (46.2% of deaths). N-terminal pro B-type natriuretic peptide (NT-proBNP) and Creatine kinase (CK) increased significantly during ICI therapy. In univariable Cox analysis, each doubling of CK was associated with higher all-cause mortality (HR 1.22 per doubling, 95% CI 1.01-1.47; P = 0.038). CONCLUSIONS: In this cohort of TET patients receiving ICI therapy, myocarditis occurred frequently in thymoma patients. Overall mortality was substantial in TET patients, with nearly half of the deaths attributable to cardiovascular causes. These findings highlight the need for vigilant cardiovascular monitoring in all TET patients undergoing ICI therapy and warrant confirmation in larger multicenter studies.
Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.
Qin X, Zhong H, Liu M … +7 more , Yu T, Ma R, Zhou Y, Chen J, Liu F, Wang X, Long J
Cancer Immunol Immunother · 2026 Apr · PMID 41925872 · Full text
Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and...
Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance γδ T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of γδ T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in γδ T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored γδ T cell function. Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.
Integrated spatial transcriptomics and pan-cancer XGBoost modeling uncover spatial drivers of immune exclusion and predict immunotherapy response.
Zhao H, Liu W, Xu H … +4 more , Wang L, Chen Z, Sun Y, Wang L
Cancer Immunol Immunother · 2026 Apr · PMID 41925746 · Full text
Immunotherapy has revolutionized cancer treatment, yet characterizing the spatial complexity of the tumor immune microenvironment remains a challenge. In this study, we established a comprehensive computational framework...
Immunotherapy has revolutionized cancer treatment, yet characterizing the spatial complexity of the tumor immune microenvironment remains a challenge. In this study, we established a comprehensive computational framework integrating multi-omics profiling across 27 cancer types to decode immune-related non-coding RNA regulatory networks. Moving beyond traditional bulk analysis, we utilized spatial transcriptomics to dissect the spatial localization of these regulators. We identified the SNHG6-BIRC5 axis as a critical driver of the "immune-cold" phenotype in lung adenocarcinoma. We provide visual evidence that this axis localizes to tumor nests and negatively correlates with T- cell infiltration, elucidating a mechanism of spatial immune exclusion. Validating the clinical relevance of these findings, genome-scale CRISPR-Cas9 screening data confirmed the functional essentiality of these targets for cancer cell survival. Furthermore, pharmacogenomic analysis revealed that high expression of this axis correlates with sensitivity to chemotherapy agents like Vinblastine, suggesting a potential stratification strategy for patients with immune-excluded tumors. To expand the clinical utility to immunotherapy prediction, we developed a pan-cancer XGBoost machine learning model incorporating 14 high-performance regulatory features. This model achieved robust performance in distinguishing immunotherapy responders from non-responders with an AUC of 0.771, outperforming traditional markers such as PD-L1. Collectively, this study highlights spatial determinants of immune exclusion and chemotherapy sensitivity- and presents a generalized machine- learning tool for precision immunotherapy stratification. The developed online resource is freely available to facilitate community-wide biomarker discovery.
An innovative treatment for lung cancer using gene-engineered human-induced pluripotent stem cell-derived natural killer cells.
Sato Y, Goto K, Yagishita S … +14 more , Miyata K, Uesugi N, Torisawa YS, Naritomi Y, Takahashi R, Sho R, Takeno Y, Kurachi K, Yamada M, Higashi Y, Kimura H, Hamada A, Nishigaki F, Tamura K
Cancer Immunol Immunother · 2026 Mar · PMID 41915242 · Full text
Various therapeutic approaches have been developed for lung cancer, including chemotherapy, radiation therapy, and immune checkpoint inhibitors. However, these approaches, including chimeric antigen receptor (CAR)-T cell...
Various therapeutic approaches have been developed for lung cancer, including chemotherapy, radiation therapy, and immune checkpoint inhibitors. However, these approaches, including chimeric antigen receptor (CAR)-T cell therapy, have shown limited efficacy against solid tumors, especially in advanced disease.To enhance the therapeutic effect, we focused on the multiple effects of a new modality of cell therapy and created engineered natural killer (eNK) cells, which are gene-engineered induced pluripotent stem cell (iPSC)-derived NK cells armed with CC motif ligand 19 (CCL19), CC chemokine receptor type 2B (CCR2B), high-affinity cluster of differentiation 16 (CD16), interleukin (IL)-15, and natural killer group 2, member D (NKG2D)-DNAX-activating protein 10 (DAP10) complex. In vitro studies showed that eNK cells exhibit significant long-lasting cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) against human lung cancer cell lines. In vivo, eNK cells achieved near-complete tumor regression in orthotopic and subcutaneous cell line-derived xenograft (CDX) models. In contrast, in patient-derived xenograft (PDX) models, eNK cells demonstrated modest tumor growth inhibition (28% reduction) as monotherapy and significantly enhanced efficacy (53% inhibition) in combination with cetuximab via antibody-dependent cellular cytotoxicity. In treated PDX tumors, human CD45-positive cells were detected within the tumor parenchyma, supporting intratumoral presence of administered human cells.These findings support the potential contribution of the five-gene modifications in enhancing tumor homing, persistence, and cytotoxicity in solid tumor treatment. This study underscores the potential of eNK cells as a novel, "off-the-shelf" allogeneic therapy for refractory solid tumors, including lung cancer.
Fungal immunomodulatory proteins skew macrophages towards a pro-inflammatory and tumour inhibitory phenotype.
Liu Y, Krzysica PA, Li Z … +3 more , Wichers HJ, Bastiaan-Net S, Hoppenbrouwers T
Cancer Immunol Immunother · 2026 Mar · PMID 41915238 · Full text
BACKGROUND: Tumour-associated macrophages (TAMs) are associated with poor clinical outcome in cancer patients, making them key targets in immunotherapy. TAMs mainly consist of anti-inflammatory M2 macrophages promoting t...
BACKGROUND: Tumour-associated macrophages (TAMs) are associated with poor clinical outcome in cancer patients, making them key targets in immunotherapy. TAMs mainly consist of anti-inflammatory M2 macrophages promoting tumour growth, metastasis and immunosuppression. Fungal immunomodulatory protein from Nectria haematococca (FIP-nha) is a potential anti-tumour agent, notably inhibiting tumour cells and exerting immunomodulatory activity on macrophages. However, the anti-tumour activity of FIP-nha via TAMs modulation is still unclear. Here, the immunomodulatory activity of rFIP-nha on M1 and M2 macrophages was explored, as well as its anti-tumour activity via macrophage modulation, using M2 macrophages as TAM representatives, through an intricate co-culture design with A549 lung cancer cells. METHODS: THP-1-monocyte derived M2 macrophages were treated with rFIP-nha and analysed phenotypically. Subsequently, rFIP-nha treated M2 macrophages were co-cultured with A549 cells to investigate anti-tumour activity via macrophage modulation. RESULTS: rFIP-nha exposure decreased macrophages phagocytosis activity, enhanced IL-1β, IL-12 and IL-10 cytokine secretion, and modulated specific cell surface markers for M2 (CD163 and CD206) towards those that are typical for M1 (CD68 and CD80) polarization. rFIP-nha treated M2 macrophages polarized towards a tumour inhibitory phenotype which, when co-cultured with A549 cells, resulted in greater reduction of tumour cell proliferation compared to A549 cells co-cultured with M2 or M1 macrophages. Moreover, rFIP-nha exacerbated tumour inhibition and cell death. CONCLUSION: rFIP-nha inhibited tumour growth in two distinct ways, by targeting tumour cells directly and by directing macrophage polarization towards a tumour inhibitory phenotype. This dual bioactivity makes FIP-nha interesting as an additive support in cancer immunotherapy.
Catgut implantation at acupoints improves anti-PD-1 inhibitor efficacy in lung cancer by inducing immune responses and remodeling the tumor microenvironment.
Wu Q, Su T, Zhang Y … +4 more , Xiong Y, Hu X, Shao L, Chen S
Cancer Immunol Immunother · 2026 Mar · PMID 41915222 · Full text
While anti-programmed death-1 (anti-PD-1) therapy has revolutionized lung cancer treatment, its efficacy remains limited by an immunosuppressive tumor microenvironment (TME). We therefore investigated whether combining a...
While anti-programmed death-1 (anti-PD-1) therapy has revolutionized lung cancer treatment, its efficacy remains limited by an immunosuppressive tumor microenvironment (TME). We therefore investigated whether combining anti-PD-1 inhibitor with catgut embedding at the Zusanli acupoint (CIAA) could enhance anti-tumor immunity by reprogramming the TME in a lung cancer mouse model. Combining in vivo tumor monitoring, multi-parametric immune profiling (flow cytometry, IHC, ELISA), and multi-omics analyses (transcriptomics and metabolomics), we found that the combination therapy was associated with enhanced tumor growth inhibition. This effect correlated with a comprehensive TME transformation: conversion to an immunologically active state with increased effector immune cell infiltration (CD8⁺ T, CD4⁺ T, B cells, macrophages) and decreased regulatory T cells, coupled with suppression of pro-tumorigenic factors (VEGF, IL-6). Integrated omics analysis suggests that the combined treatment may modulate tumor-stroma interaction pathways (e.g., PI3K-Akt, focal adhesion) and rewire immunometabolic networks (e.g., tryptophan metabolism). Our study provides hypothesis-generating correlative data positioning CIAA as a potential adjunct capable of remodeling the TME to potentiate anti-PD-1 therapy in lung cancer.
Haemostatic changes during CART cell therapy and risk of complications.
Panizo-Inogés M, Marcos-Jubilar M, González-Porras JR … +10 more , Puerta-Vazquez C, Fernández-Arias C, Rodríguez-Otero P, Alfonso-Pierola A, Villar S, Canales MÁ, Orbe J, Páramo JA, Prósper F, Lecumberri R
Cancer Immunol Immunother · 2026 Mar · PMID 41915216 · Full text
Chimeric antigen receptor T cell (CART) therapy toxicity includes cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), but also thrombotic and haemorrhagic events. Given the li...
Chimeric antigen receptor T cell (CART) therapy toxicity includes cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), but also thrombotic and haemorrhagic events. Given the link between haemostasis and inflammation, haemostatic biomarkers could help identify at-risk patients. Sixty-two adult patients receiving CD19- or BCMA-targeted CART were prospectively included and followed up for 30 days to characterize haemostatic changes and evaluate their association with the risk of CRS, ICANS, thrombosis and bleeding. Blood samples were collected at baseline (pre-lymphodepletion), pre-infusion and on days + 3, + 14, and + 28 post-infusion. Haemostatic tests, including thrombin generation assay (TGA, ST-Genesia) and P-Selectin, were performed. CRS occurred in 94% of patients, ICANS in 39%, venous thrombosis in 1.6%, and clinically relevant bleeding in 13%. During follow-up, prolonged coagulation times, thrombocytopenia and decreased fibrinogen and P-selectin, were noted. Baseline endogenous thrombin potential (ETP) was associated with clinically relevant CRS risk (OR 12.39; p = 0.02) and baseline C-reactive protein (CRP) with ICANS (OR 1.66; p < 0.01). Baseline P-selectin levels and platelet count identified patients at higher bleeding risk (OR 0.20; p = 0.03 and OR 0.39; p < 0.01, respectively). In the first month after CART infusion, bleeding incidence exceeds thrombosis. TGA, CRP, platelet count and P-selectin may help identify patients at risk of severe toxicity, enabling earlier, targeted interventions.
Circular RNAs in cancer: Its biogenesis, functions, relationships with cancer progression, applications in immunotherapy and biomarker potentials.
Gao Y, Xu L, Sun R … +7 more , Gao L, Yan P, Yang X, Wang G, Xian Y, Zhang J, Zhu D
Cancer Immunol Immunother · 2026 Mar · PMID 41915211 · Full text
Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs generated via backsplicing. They are highly stable and evolutionarily conserved, making them promising candidates for cancer therapy and diagnosis. Cir...
Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs generated via backsplicing. They are highly stable and evolutionarily conserved, making them promising candidates for cancer therapy and diagnosis. CircRNAs regulate cancer progression by modulating genome instability, angiogenesis, metastasis, stemness, and chemoresistance. They do so through mechanisms including microRNA (miRNA) sponging, protein interaction, translational templating, and transcription/translation regulation. CircRNAs play a critical role in cancer immunotherapy. They modulate immune checkpoint blockade (ICB) responses and cytokine secretion to reshape the tumor immune microenvironment (TME). CircRNAs also serve as stable platforms for neoantigen-based cancer vaccines and improve in vivo chimeric antigen receptor T cell (CAR-T) therapy by replacing unstable linear mRNA. Additionally, circRNAs are potential noninvasive biomarkers due to their abundance in body fluids and differential tumor-normal expression. Despite challenges such as unclear regulatory networks, off-target effects, and inefficient delivery, this review systematically summarizes the biogenesis of circRNAs, their functional mechanisms, their roles in cancer progression, and their applications in cancer immunotherapy. The review also highlights their utility as biomarkers and future translational directions, providing a focused overview of their potential to advance cancer immunotherapy.
Allogeneic CD56 + cell infusion as a bridge to hematopoietic stem cell transplantation in relapsed/refractory acute myeloid leukemia: a phase I clinical trial.
Ghasabeh AS, Izadpanah A, Bakhtiyaridovvombaygi M … +8 more , Seresht-Ahmadi M, Parkhideh S, Seraji HR, Sabri A, Yazdanparast S, Hajifathali A, Gharehbaghian A, Roshandel E
Cancer Immunol Immunother · 2026 Mar · PMID 41915180 · Full text
BACKGROUND AND PURPOSE: Acute myeloid leukemia (AML) is an aggressive disease with suboptimal overall survival, especially in relapsed/refractory patients. The primary goal of salvage therapy in this patient is to achiev...
BACKGROUND AND PURPOSE: Acute myeloid leukemia (AML) is an aggressive disease with suboptimal overall survival, especially in relapsed/refractory patients. The primary goal of salvage therapy in this patient is to achieve optimal disease control, thereby allowing the transition to hematopoietic stem cell transplantation (HSCT), which remains the only curative option for a subset of these patients. Allogeneic KIR ligand-mismatched CD56 NK/NKT-like cells have demonstrated antileukemic activity and represent a promising platform for the development of novel cellular therapies. STUDY DESIGN: Relapsed/refractory non-M3 AML patients who were not HSCT candidates were included in this phase I clinical trial. Patients received the FLAG conditioning regimen followed by three escalating doses (1 × 10⁶, 3 × 10⁶, 5 × 10⁶ cells/kg) of CD56 NK/NKT-like cells at 5-day intervals. RESULTS: A total of 11 patients with a median age of 41.5 years were enrolled in the study. On average, they received three lines of prior chemotherapy and showed 18% blasts in their bone marrow. The infusion of CD56⁺ NK/NKT-like cells was safe, with no serious toxicity or graft-versus-host disease (GVHD) observed in any patient. Following this treatment protocol, five patients (45.4%) achieved complete remission (CR), with or without hematologic count recovery. Four of these patients (36.3%) underwent successful HSCT and remained event-free to the end of the follow-up period. CONCLUSION: Overall, these trials indicated that the FLAG regimen chemotherapy combined with allogeneic KIR ligand-mismatched CD56 NK/NKT-like cell infusion is safe and may serve as an effective bridge to HSCT in 36.3% of patients with refractory/relapsed non-M3 AML.
Mass cytometry uncovers distinct blood myeloid phenotypes linked to clinical responses during gastric cancer chemoimmunotherapy.
Lim SH, An M, Heo YJ … +3 more , Cha JH, Kim ST, Lee J
Cancer Immunol Immunother · 2026 Mar · PMID 41915048 · Full text
Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy has reshaped metastatic gastric cancer (GC) treatment, improving response rate, progression-free survival, and overall survival. We aimed to e...
Combination therapy with immune checkpoint inhibitors (ICIs) and chemotherapy has reshaped metastatic gastric cancer (GC) treatment, improving response rate, progression-free survival, and overall survival. We aimed to explore circulating immune cells and elucidate the mechanisms underlying the therapeutic effects of pembrolizumab and capecitabine/oxaliplatin (XELOX) in patients with metastatic GC. Potential immune mechanisms in GC tumors were retrospectively examined among patients from our phase 2 chemoimmunotherapy trial. Peripheral blood samples from patients with GC undergoing first-line pembrolizumab plus XELOX therapy were monitored using high-dimensional cytometry. Matched paired-tissue single-cell RNA-seq data were analyzed. Samples were collected from 24 patients at baseline, after one cycle of XELOX (FU1), and 18 weeks after pembrolizumab addition (FU2). Natural killer cell (CD3-NCAM +) and myeloid cell (CD11c + or CD14 +) subsets increased during chemoimmunotherapy.-At FU1, the proportion of PBMC monocytes was significantly higher in responders compared to non-responders. Consistent with the increase in monocyte-derived macrophages (M1-like) in paired tissues, monocytes in peripheral blood mononuclear cells increased at FU1. Immunosenescence score revealed recently mobilized monocytes infiltrating the tumor bed after chemotherapy. Gene expression analysis showed significantly upregulated CXCL8, CCL3, and CCL4 in FU1 responders. Early elevation of circulating monocytes correlated with better survival. After adding pembrolizumab, memory CD8 (CD3 + CD8 + CD27 + CD28 + CD45RO +) T cells increased in responders compared to non-responders. Our results elucidate the serial immunological landscape underpinning favorable responses to first-line ICI plus chemotherapy in patients with gastric cancer. Early distinct changes in blood myeloid cells during chemotherapy can be used to assess clinical response.
Downregulation of B7-H4 contributes to the synergistic effect of USP2a-targeted/anti-PD-1 combination therapy in EGFR mutant lung cancer.
Sun B, Kong M, Jiang X … +9 more , Zhu L, Zhang J, Tan L, Wang C, Yuan Z, Chen S, Wang C, Jiang Y, Zhang L
Cancer Immunol Immunother · 2026 Mar · PMID 41885940 · Full text
Anti-PD-1 treatment has shown clinical benefit in malignant cancers. However, EGFR-mutant (EGFR-MT) lung adenocarcinoma, an immune-cold tumor, shows poor response to this immunotherapy. This scenario is associated with e...
Anti-PD-1 treatment has shown clinical benefit in malignant cancers. However, EGFR-mutant (EGFR-MT) lung adenocarcinoma, an immune-cold tumor, shows poor response to this immunotherapy. This scenario is associated with elevated levels of B7-H4, an immune checkpoint demonstrating CD8 T cell inhibition activity. Our previous study has revealed that deubiquitinase USP2a could stabilize B7-H4 protein. Therefore, we further explore whether USP2a inhibition could remodel immune-cold microenvironment in this study. First, we confirmed that USP2a inhibitors effectively promoted proteasomal degradation of B7-H4 through blocking its deubiquitination process. To rule out the possiblity that USP2a might directly inhibit EGFR MT endocytosis so as to inhibit B7-H4 expression,we investigated the effect of USP2a inhibitor ML364 on EGFR mutants protein levels. It showed that ML364 did not inhibit EGFR mutant protein levels. ML364 could directly inhibit tumor cell proliferation in vitro. In immune-deficient nude mice ML364 inhibited tumor growth through inhibiting USP2a substrates Cyclin D1 and MDM2. In immune-competent C57BL/6 mouse model, ML364 could downregulate B7-H4 level thereby repress tumor growth through remodeling immune-cold microenvironment. Finally, we proved that ML364 could sensitize tumor to anti-PD-1 therapy in immune-competent mice. Immunohistochemical staining analysis showed that ML364 could inhibit B7-H4 expression, thereby enhanced Qa-1b (homolog of HLA-E in mouse) expression and CD8 T cell infiltration. This study proved that inhibition USP2a could suppress tumor growth through two mechanisms: directly inhibiting tumor cell proliferation and remodel immune-cold microenvironment. Therefore, inhibiting USP2a could sensitize tumor to anti-PD-1 therapy.
Clinical characteristics, prognostic factors, and feasibility of ICI continuation in immune checkpoint inhibitor-related pneumonitis.
Masumoto K, Tsubouchi K, Matsukane R … +5 more , Yasukochi S, Ogata H, Takano T, Uchida M, Okamoto I
Cancer Immunol Immunother · 2026 Mar · PMID 41885927 · Full text
PURPOSE: Immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-pneumonitis) is a serious complication, whose clinical course and optimal management strategies remain inadequately elucidated. This study clarified whe...
PURPOSE: Immune checkpoint inhibitor (ICI)-related pneumonitis (ICI-pneumonitis) is a serious complication, whose clinical course and optimal management strategies remain inadequately elucidated. This study clarified whether post-pneumonitis ICI continuation is safe and feasible, identified risk factors for fatal outcomes or successful continuation, and assessed whether findings from patients with lung cancer can be generalized to those with other malignancies. METHODS: This retrospective study analyzed data from 1,320 patients who received ICI therapy at Kyushu University Hospital between September 2014 and March 2023. Among these, 300 and 1,020 patients had lung and non-lung cancers, respectively. Clinical characteristics, treatment strategies, and outcomes were compared between the two groups. Predictors of fatal pneumonitis and successful ICI continuation were identified using univariable logistic regression. RESULTS: ICI-pneumonitis occurred in 96 (7.3%) patients, with a higher incidence in those with lung cancer (14.0%, [42/300]) than in those with non-lung cancers (5.3%, [54/1020]). Clinical characteristics remained similar across cancer types post-pneumonitis. Diffuse alveolar damage pattern, grade ≥ 3 pneumonitis at diagnosis, and elevated C-reactive protein level were significant predictors of fatal pneumonitis. Among 34 patients who attempted ICI continuation, 20 (58.8%) maintained ICI treatment until disease progression. Successful ICI continuation showed a trend toward association with normal baseline lung parenchyma. CONCLUSIONS: The similar characteristics of ICI-pneumonitis across malignancies support the generalizability of management strategies. Approximately one-fifth of patients successfully continued ICI therapy after pneumonitis. Systematic radiological surveillance and appropriate severity-based treatment may help optimize outcomes in patients receiving ICI therapy.
A novel humanized immune stroma PDX cancer model for therapeutic studies.
Yang D, Beddows I, Tang H … +13 more , Bai S, Cascio S, McGonigal SC, Johnson BK, Powers JJ, Acharya R, Bao R, Bruno TC, Soong TR, Conejo-Garcia JR, Shen H, Bility MT, Buckanovich RJ
Cancer Immunol Immunother · 2026 Mar · PMID 41874706 · Full text
Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To a...
Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, using patient-derived tumor cells, patient-derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a human stroma-patient-derived xenograft (HS-PDX) tumor model. HS-PDX, compared to the standard PDX model, demonstrates greater resistance to targeted therapy and chemotherapy and better reflect patient response to therapy. Furthermore, HS-PDX can be grown in mice with humanized bone marrow to create humanized immune stroma patient-derived xenograft (HIS-PDX) models. The HIS-PDX model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on recruitment of TAMs and tumor immune exclusion to impact to response to immunologic therapy. We show an immunosuppressive role for human tumor stroma and that this model can be used to identify immunotherapeutic combinations to overcome stroma-mediated immunosuppression. Combined, our data confirm a critical role for human stroma in therapeutic response and indicate that HIS-PDX can be an important tool for preclinical drug testing.
Immunological effects of amivantamab in EGFR or MET-expressing non-small cell lung cancer.
Yoshichika R, Mukohara F, Yamada K … +8 more , Nagasaki J, Watanabe H, Ueda Y, Suzawa K, Shien K, Toyooka S, Ishino T, Togashi Y
Cancer Immunol Immunother · 2026 Mar · PMID 41874698 · Full text
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MET proto-onc...
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MET proto-oncogene, receptor tyrosine kinase (MET), has demonstrated clinical benefit in EGFR-mutant NSCLC through dual blockade, but its immunological role in human clinical specimens, especially tumor-infiltrating lymphocytes (TILs), has not been directly evaluated. METHODS: We analyzed surgically resected tumor samples from 40 patients with NSCLC to investigate immune responses and their associations with EGFR and MET expression. TILs were characterized by flow cytometry (FCM) and immunohistochemistry (IHC). To assess the immunomodulatory potential of amivantamab, fresh tumor digests containing live tumor cells and TILs were cultured ex vivo with CD3 and CD28 stimulation in the absence or presence of amivantamab, followed by FCM. EGFR and MET expression were also evaluated by IHC. RESULTS: EGFR mutations and high EGFR protein expression were associated with a trend toward reduced CD8⁺ T-cell and dendritic cell (DC) infiltration. In ex vivo TIL assays, exposure to amivantamab significantly activated CD8⁺ T cells, such as programmed cell death-1 expression and cytokine production, and promoted DC maturation. These effects were most pronounced in tumors with high EGFR or MET protein expression rather than EGFR mutations. CONCLUSIONS: This study provides the first direct evidence from ex vivo fresh TIL assays using human NSCLC clinical specimens that amivantamab can activate immune responses. EGFR and MET expression may serve as potential biomarkers for amivantamab-induced immune responses.
Outcomes in patients with refractory/relapsed CNS lymphoma treated in complete remission: autologous transplantation vs. CAR-T therapy.
Yang F, Liu R, Fu Z … +8 more , Guo Y, Ma L, Cao M, Deng B, Wu H, Chen C, Ke X, Hu K
Cancer Immunol Immunother · 2026 Mar · PMID 41874671 · Full text
BACKGROUND: Autologous hematopoietic cell transplantation (ASCT) is a reasonable consolidation therapy for eligible patients with chemosensitive relapsed central nervous system lymphoma (CNSL) who have achieved complete...
BACKGROUND: Autologous hematopoietic cell transplantation (ASCT) is a reasonable consolidation therapy for eligible patients with chemosensitive relapsed central nervous system lymphoma (CNSL) who have achieved complete remission (CR) and maintained the CR. Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment option for patients with relapsed CNSL, although evidence on outcomes in patients who achieve CR is limited. AIM: To compare the efficacy of ASCT versus CAR-T therapy as consolidation therapy in patients with relapsed CNSL once CR had been re-achieved. METHODS: A retrospective observational study was conducted on patients who underwent ASCT or CAR-T therapy at the Department of Lymphoma, Beijing Gobroad Hospital, between 2021 and 2024. CAR-T therapy was part of the clinical trial "Different B-cell-targeted CAR-T cells for relapsed/refractory CNSL (ChiCTR2200058972)". RESULTS: Sixty patients, including 42 (70%) with primary CNSL and 18 (30%) with diffuse large B-cell lymphoma (DLBCL) with secondary CNS involvement, were enrolled. The median follow-up duration was 12.1 months (1.28-59.9 months). Compared with patients in the CAR-T group, patients who received ASCT while in CR had superior progression-free survival (PFS) [3-year PFS 80% (95% CI: 48.4-93.4) vs. 64.8% (95% CI: 38.9-81.9); P = 0.026] and a lower cumulative incidence of relapse/progression [3-year relapse rate 20% (95% CI: 4.12-44.39) vs. 30.2% (95% CI: 11.0-52.2); P = 0.038]. CONCLUSION: Compared with CAR-T therapy, ASCT was associated with improved PFS in patients with relapsed CNSL who had achieved CR.
Risk factors for immune checkpoint inhibitor colitis: a retrospective multi-center cohort study using electronic health records.
Chu DHT, Schalkamp AK, Rudrapatna VA
Cancer Immunol Immunother · 2026 Mar · PMID 41874669 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective for many cancers but often cause immune-related adverse events, particularly gastrointestinal (GI) complications such as colitis. Identifying risk factors for...
BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective for many cancers but often cause immune-related adverse events, particularly gastrointestinal (GI) complications such as colitis. Identifying risk factors for ICI colitis (CIC) could improve patient selection and discover potential mechanisms relevant to idiopathic inflammatory bowel disease (IBD). We aim to identify risk factors with a robust methodological approach in a large multi-center longitudinal cohort. METHODS: We used electronic health record data from six University of California institutions with 10,260 adults on ICIs. Baseline and time-varying predictors were defined based on prior IBD epidemiology studies, including interactions. LASSO Cox regression was applied to data from UCSF Central Data Warehouse to select the most predictive model, with coefficients estimated using multi-center data. RESULTS AND CONCLUSION: Fourteen significant predictors of CIC were identified. The strongest predictors were concurrent use of antibiotics (HR 2.72, 95% CI: 2.41-3.07) and non-steroid anti-inflammatory drugs (1.50, 1.16-1.94). Notable GI risk factors included gastroesophageal reflux disorder (1.31, 1.14-1.50), other GI disorders (1.32, 1.16-1.50), and disorders of the gallbladder, biliary tract, and pancreas (1.33, 1.15-1.57). High BMI before ICI administration increased risk (per unit 1.07, 1.04-1.09), while higher BMI after ICI administration decreased risk (per unit 0.93, 0.90-0.95). Melanoma, anxiety, and depression also increased risk. GI oncologists should consider ICI colitis in patients with comorbid GI disorders or those using antibiotics or NSAIDs. A routine checkup for colitis could be beneficial for those patients. Future studies are needed to explore the underlying mechanisms and quantify clinical impact of increased checkups for colitis.
Heterogeneity and prognostic significance of mast cell subsets in the tumor microenvironment of prostate cancer.
Fang R, Zhao S, Si M … +3 more , Zhang Y, Xu R, Li J
Cancer Immunol Immunother · 2026 Mar · PMID 41874654 · Full text
BACKGROUND: Prostate cancer (PC) is one of the malignant tumors with high incidence and mortality worldwide in men. Immune cells in the tumor microenvironment (TME), particularly mast cells, play important roles in tumor...
BACKGROUND: Prostate cancer (PC) is one of the malignant tumors with high incidence and mortality worldwide in men. Immune cells in the tumor microenvironment (TME), particularly mast cells, play important roles in tumor progression and prognosis. However, the dual roles of mast cells in PC have not been fully elucidated. METHODS: In this study, single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing, and bioinformatics analyses were performed to investigate the heterogeneity of mast cell subsets in the TME of PC and their association with prognosis. Single-cell data from 39 PC tumor samples were analyzed, and prognostic prediction was validated using datasets including HMU, TCGA, and MSKCC cohorts. Non-negative matrix factorization was applied to cluster mast cell subsets, followed by analyses of subset-specific gene markers, transcription factor activity, and biological pathways. Survival analysis and ROC curve evaluation were conducted to assess prognostic value. RESULTS: Mast cells in the TME of PC were classified into two distinct subsets, each characterized by unique gene markers and functional pathways. Mast cell1 was highly associated with pro-tumorigenic pathways, whereas mast cell2 predominantly exhibited antitumor immune regulatory properties. High expression of mast cell1 signatures was correlated with poorer survival outcomes, while high expression of mast cell2 signatures was associated with better survival. Key marker genes such as BIRC3 and FOS were identified as potential prognostic factors, high BIRC3 expression was significantly associated with unfavorable prognosis, whereas high FOS expression correlated with favorable prognosis. CONCLUSION: This study revealed functional heterogeneity of mast cell subsets in the TME of PC and their distinct roles in tumor progression. The identification of subset-specific marker genes provides novel molecular targets for clinical diagnosis, prognostic prediction, and personalized therapy in PC.
Real-world effectiveness of avelumab, pembrolizumab, and enfortumab vedotin in patients with advanced urothelial carcinoma with squamous differentiation (ARON-2EV).
Mollica V, Massari F, Fujita K … +28 more , Giannatempo P, Grande E, Büttner T, Bourlon MT, Taha T, Fukuokaya W, Myint ZW, Pichler R, Binz K, Molina-Cerrillo J, Kopecky J, de Liaño AG, Kucharz J, Fiala O, Matrana MR, Kopp RM, Di Civita MA, Zgura A, Ansari J, Kihnel R, De Felice F, Angel M, Monteiro FSM, Soares A, Urun Y, Buti S, Santini D, Santoni M
Cancer Immunol Immunother · 2026 Mar · PMID 41874648 · Full text
INTRODUCTION: Avelumab, pembrolizumab, and enfortumab vedotin (EV) demonstrated efficacy in mUC following platinum-based chemotherapy. However, real-world data in patients with urothelial carcinoma with squamous differen...
INTRODUCTION: Avelumab, pembrolizumab, and enfortumab vedotin (EV) demonstrated efficacy in mUC following platinum-based chemotherapy. However, real-world data in patients with urothelial carcinoma with squamous differentiation (UCSD) are limited. The aim of this study is to assess the real-world clinical outcomes of avelumab, pembrolizumab, or EV in mUCSD patients. MATERIALS AND METHODS: The ARON-2EV study is a retrospective, international, multicenter analysis in patients with mUC treated with avelumab, pembrolizumab, or EV across 79 centers in 21 countries. Patients were divided into three cohorts: 1 (avelumab), 2 (pembrolizumab), and 3 (EV). Primary endpoints were overall survival (OS) and time on treatment (ToT). Secondary objectives included evaluating clinical factors associated with outcomes and exploring the impact of UCSD histology on response to therapy. Statistical methods included Kaplan-Meier estimates, log-rank tests, Fisher's exact and chi-square tests, and Pearson's correlation coefficients. RESULTS: A total of 1918 patients, 1696 with advanced pure UC (pUC) and 222 with mUCSD (36 in cohort 1, 111 in cohort 2, and 75 in cohort 3), were included. Median OS was shorter in patients with UCSD compared to patients with pUC histology in the three cohorts (1: 13.0 vs 26.8 months, HR 2.66, p = 0.003; 2: 10.2 vs 18.5 months, HR 1.52, p = 0.008; and 3: 7.6 vs 13.1 months, HR 1.68, p = 0.011). Median ToT was shorter in patients with UCSD compared to patients with pUC histology in cohort 1 (3.5 vs 5.6 months, HR 1.57, p = 0.044) and 3 (7.6 vs 13.6 months, HR 1.83, p = 0.005) but not in cohort 2 (3.7 vs 4.7 months, HR 1.19, p = 0.177). Response to therapy was negatively correlated with UCSD histology in cohorts 2 (correlation coefficient 0.094, p = 0.008) and 3 (correlation coefficient 0.107, p = 0.021), while response to avelumab was not correlated with UCSD (correlation coefficient 0.072, p = 0.263). CONCLUSIONS: UCSD is a histology with a poor prognosis and response to treatments compared to pUC. Treatments activity and effectiveness in divergent differentiations should be addressed in dedicated prospective studies. TRIAL REGISTRATION NUMBER: NCT05290038.
RARRES1 marks an immune-cold, chemoresistance-associated malignant epithelial subpopulation enriched in pancreatic ductal adenocarcinoma.
Ge H, Zhou J, Ghadban T … +5 more , Wolters-Eisfeld G, Hackert T, Wang D, Liu W, Güngör C
Cancer Immunol Immunother · 2026 Mar · PMID 41854891 · Full text
BACKGROUND: Pancreatic ductal adenocarcinoma is characterized by therapy resistance and an immunosuppressive microenvironment. This study investigated the cellular mechanisms underlying chemotherapy resistance and immune...
BACKGROUND: Pancreatic ductal adenocarcinoma is characterized by therapy resistance and an immunosuppressive microenvironment. This study investigated the cellular mechanisms underlying chemotherapy resistance and immune evasion in PDAC, focusing on identifying key malignant epithelial subpopulations and their molecular drivers. METHODS: We analyzed scRNA-seq data from 27 samples, including treatment-naive and chemotherapy-exposed primary tumors and liver metastasis. Analysis included CNV inference, gene set enrichment, cell-cell communication, NMF analysis and drug sensitivity prediction. Validation employed gemcitabine-resistant cells, western blotting and pan-cancer survival analysis of TCGA/ICGC data. RESULTS: We identified a malignant epithelial subcluster enriched in progressive disease samples and liver metastasis. This subcluster exhibited an immune-cold phenotype, characterized by disrupted communication with immune cells, increased immunosuppressive regulatory T cells and exclusion of anti-tumor effector cells. Further, it was associated with activated oncogenic and chemoresistance pathways, multi-drug resistance to standard therapies, higher tumor mutational burden and increased KRAS mutation frequency. RARRES1 was nominated as a core upregulated gene in this subpopulation. Functional studies confirmed RARRES1 overexpression in gemcitabine-resistant cells, and pan-cancer analysis established RARRES1 as a new biomarker for poor prognosis across multiple cancer types. CONCLUSIONS: Our work defines a chemotherapy-resistant and metastasis-enriched malignant epithelial subpopulation in PDAC that drives disease progression through an immune-cold niche. We identify RARRES1 as a pivotal regulator of this process, contributing to both therapy resistance and immune exclusion, and propose it as a novel pan-cancer prognostic biomarker. These findings reveal a targetable cellular mechanism underlying poor treatment response in PDAC.
Correction: Nattokinase-driven remodeling of tumor microenvironment enhances the efficacy of MSLN-targeted CAR-T cell therapy in solid tumors.
Zhao L, Zhang Y, Yang X … +3 more , Chen T, Liu J, Guo Z
Cancer Immunol Immunother · 2026 Mar · PMID 41848865 · Full text
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