Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Efficacy and safety of anti-PD-1-based therapies in advanced melanoma across acral and mucosal subtypes: a nationwide retrospective cohort study.
Qiao Y, Fu X, Hussain I … +20 more , Ge W, Yang W, Jiang R, Dai X, Chen H, Zhao J, Tang M, Mu F, Wang H, Wu Q, Xia X, Zhang Y, Ji S, Xu Y, Cao X, Wang J, Gao L, Wang J, Yao Y, Fang Y
Cancer Immunol Immunother · 2026 Jun · PMID 42334611 · Publisher ↗
BACKGROUND: Acral melanoma (AM) and mucosal melanoma (MM) respond poorly to anti-PD-1 monotherapy. Therefore, there is an urgent need to explore safe and effective anti-PD-1-based combined therapies. METHODS: A nationwid...
BACKGROUND: Acral melanoma (AM) and mucosal melanoma (MM) respond poorly to anti-PD-1 monotherapy. Therefore, there is an urgent need to explore safe and effective anti-PD-1-based combined therapies. METHODS: A nationwide real-world cohort study consecutively included patients with advanced melanoma treated with anti-PD-1 in China between July 1, 2018, and June 30, 2023. The Research Electronic Data Capture (REDCap) system was used across all centers. The primary endpoints were progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs), with a secondary endpoints of objective response rate (ORR). Multivariable Cox and logistic regression models were conducted to compare the efficacy and safety of different anti-PD-1-based combination therapies with anti-PD-1 monotherapy. Stratified analyses were performed to evaluate the effect of therapies in cutaneous, acral, mucosal, and unknown primary subtypes. RESULTS: A total of 431 advanced melanoma patients comprising 22% cutaneous, 39% acral, 32% mucosal, and 7% unknown primary subtypes were included. Multivariable Cox analysis indicated that compared with anti-PD-1 monotherapy, anti-PD-1 + anti-VEGF + chemotherapy (HR, 0.4 [0.2, 0.7], P = 0.005) and anti-PD-1 + anti-VEGF therapy (HR, 0.4 [0.2, 0.9], P = 0.018) showed significant PFS benefit in AM and MM, respectively. Notably, anti-PD-1 + IFN-α1b showed a nonsignificantly longer PFS and OS in AM. A multivariate logistic regression model found that anti-PD-1-based combination therapies were significantly associated with grade 1-2 irAEs, while only anti-PD-1 + IFN-α1b + anti-VEGF therapy was significantly associated with high risk of grade 3-5 irAEs (OR, 4.4 [1.3-14.7], p = 0.017), without a significant survival benefit. CONCLUSIONS: Our results provide evidence for anti-PD-1 + anti-VEGF + chemotherapy and anti-PD-1 + IFN-α1b in AM and anti-PD-1 + anti-VEGF therapy in MM, as the long-term benefit and acceptable toxicity. However, for the patients who received anti-PD-1 + IFN-α1b + anti-VEGF, cautionary notes and awareness of drug safety should be raised, as the triple therapy with multiple mechanisms may increase the potential risk of toxicity.
Smoking-associated modulation of gut microbiota shapes response to immune checkpoint inhibitors in non-small cell lung cancer.
Chien PY, Cheng WC, Hung CC … +7 more , Tu CY, Hsia TC, Cho DY, Hsueh PR, Lai ZL, Shen YC, Lin YC
Cancer Immunol Immunother · 2026 Jun · PMID 42324435 · Publisher ↗
BACKGROUND: Smoking status has been associated with differences in immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC), though the underlying mechanisms remain unclear. This prospective cohor...
BACKGROUND: Smoking status has been associated with differences in immune checkpoint inhibitor (ICI) efficacy in non-small cell lung cancer (NSCLC), though the underlying mechanisms remain unclear. This prospective cohort study evaluated whether smoking-related changes in the gut microbiota are linked to ICI response. METHODS: Baseline fecal samples from 225 patients with NSCLC were analyzed using full-length 16S rRNA sequencing. Microbial composition, predicted functional features, and clinical variables were examined in relation to treatment response and progression-free survival (PFS). Associations with treatment response were assessed using multivariable ordinal logistic regression. PFS was evaluated using Kaplan-Meier analysis and the log-rank test. RESULTS: Smoking was associated with selected taxon-level microbial differences despite no significant differences in alpha or beta diversity. Compared with never-smokers, smokers exhibited reduced abundance of Bifidobacterium longum and enrichment of Gram-negative taxa. Functional prediction indicated increased potential for lipopolysaccharide, Kdo₂-lipid A, and lipid IVA biosynthesis in smokers. Predicted lpxM abundance, encoding a lipid A myristoyltransferase, was positively correlated with the Gram-negative bacterial fraction. Moreover, increased abundance of lpxM-linked Gammaproteobacteria was associated with improved ICI response in the NSCLC cohort. Conversely, lower B. longum abundance was associated with favorable ICI response and prolonged PFS. CONCLUSIONS: These results indicate that smoking-related gut microbial alterations, particularly reduced B. longum abundance, are associated with enhanced ICI efficacy in NSCLC, supporting a role for the gut microbiota in smoking-associated differences in immunotherapy outcomes.
Restoring STING expression in soft tissue sarcoma increases activation and function of tumor-infiltrating lymphocytes.
Godsk SH, Crus De Los Santos M, Bjerg TW … +7 more , Andersen TG, Haglund de Flon F, Harder ME, Etzerodt A, Aggerholm-Pedersen N, Lundqvist A, Jakobsen MR
Cancer Immunol Immunother · 2026 Jun · PMID 42323747 · Publisher ↗
Sarcomas are rare, highly heterogeneous malignancies, with soft tissue sarcomas (STS) comprising nearly 80 histological subtypes. Localized STS is generally treated with surgery and radiotherapy, whereas metastatic disea...
Sarcomas are rare, highly heterogeneous malignancies, with soft tissue sarcomas (STS) comprising nearly 80 histological subtypes. Localized STS is generally treated with surgery and radiotherapy, whereas metastatic disease relies largely on chemotherapy, which offers limited benefit. Although inflammation influences tumor development, treatment response, and prognosis, immune checkpoint inhibitors have shown minimal efficacy in sarcoma. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is linked to mutational burden, genomic instability, immune cell infiltration, and therapeutic response across multiple cancer types. However, its role in sarcoma remains unclear. In a newly established cohort of STS patients, we found that STING expression in primary tumors correlates with immune cell infiltration. Using a lipid nanoparticle (LNP)-mediated delivery of CRISPR activation mRNA components, we restored STING expression in STS cells, thereby reactivating cGAS-STING signaling. This promoted T‑cell recognition and tumor cell killing in both 2D and 3D patient-derived models and enhanced responses to anti-PD-1 treatment. Together, our results show that controlled epigenetic activation of STING in STS enhances immune infiltration and tumor cell killing. Targeting STING through CRISPR activation may therefore represent a promising therapeutic strategy for STS.
Oncolytic virus with an immune stimulatory payload for osteosarcoma therapy.
Khan S, Higgins TA, Shimko-Lofano I … +7 more , Sandey M, Logsdon E, Bunch G, Fatemi Y, Hoffman LMK, Smith BF, Agarwal P
Cancer Immunol Immunother · 2026 Jun · PMID 42322431 · Publisher ↗
Osteosarcoma (OS) is a highly aggressive bone malignancy that predominantly affects children and young adults. There have been no major changes in patient survival in the past four decades. Therefore, new therapeutic int...
Osteosarcoma (OS) is a highly aggressive bone malignancy that predominantly affects children and young adults. There have been no major changes in patient survival in the past four decades. Therefore, new therapeutic interventions are needed. We have developed an enhanced conditionally replicative canine oncolytic adenovirus, CAV2-AU-M3, armed with an anti-PD1 heavy-chain antibody (HcAb), and evaluated its efficacy against osteosarcoma across four canine cell lines. CAV2-AU-M3 was characterized for its infectivity, lytic properties, and anti-PD1 Ab production in monolayer and spheroid cultures. Additionally, the impact of intratumoral administration of the virus on tumor growth was measured in a mouse model. Our study demonstrates that CAV2-AU-M3 infects and lyses different canine OS cell lines at varying rates but produces anti-PD1 Ab at similar levels across all osteosarcoma cell lines. Additionally, anti-PD1 Ab produced by CAV2-AU-M3 can effectively bind the cell surface PD1 receptor and inhibit the binding of PDL1 to PD1 receptors.
Single-cell and multi-omics integration delineates the landscape of gene-wise intratumor heterogeneity and identifies prognostic biomarkers for immunotherapy in non-small cell lung cancer.
Yuan J, Weng Z, Li Z … +8 more , Chen R, Cheng C, Yang W, Xie X, Luo C, Wang T, Zhang S, Tan Z
Cancer Immunol Immunother · 2026 Jun · PMID 42322411 · Publisher ↗
BACKGROUND: Gene-wise intratumor heterogeneity (ITH), defined as spatial variability in the expression of individual genes across tumor regions, remains incompletely characterized in non-small cell lung cancer (NSCLC). I...
BACKGROUND: Gene-wise intratumor heterogeneity (ITH), defined as spatial variability in the expression of individual genes across tumor regions, remains incompletely characterized in non-small cell lung cancer (NSCLC). Identifying low-ITH genes as predictive biomarkers offers a promising strategy to enhance the reliability of immunotherapy outcome prediction. METHODS: We profiled gene-wise ITH using multi-region scRNA-seq data and a computational framework combining variance and clustering metrics. Prognostic low-ITH genes were screened via immunotherapy RNA-seq datasets and six machine learning algorithms to construct the LITHrisk score. Transcriptomic profiling and in vitro experiments elucidated the biological and functional relevance of key score components. RESULTS: The gene-wise ITH landscape in NSCLC was delineated, with several critical immune checkpoint genes, including PD-L1, LAG3, and TIM-3, being identified as low-ITH genes. A low-ITH-derived signature, the LITHrisk score (PD-L1, CDK11B, CXCL13, RPS4Y1, AKR1B10, CRLF1), effectively predicted immunotherapy prognosis and response in NSCLC and other cancers. Tumors with a low LITHrisk score were characterized by enrichment of immune response-related pathways and heightened infiltration of immune cells, such as T cells, B cells, and myeloid cells. Furthermore, we found that component genes of the score were linked to key tumor characteristics: AKR1B10 was associated with tumor immune interactions, functioning via SPP1 regulation to suppress anti-tumor immunity, while CRLF1 was implicated in promoting a fibroblast-enriched microenvironment and modulating tumor cell motility. CONCLUSION: Our study provides a practical transcriptome-based tool for advancing precision immunotherapy and nominates potential therapeutic targets for enhancing treatment efficacy.
A phase I study evaluating subcutaneous administration of the monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor cetrelimab (JNJ-63723283) in patients with advanced solid malignancies.
Rutkowski P, Kowalski DM, Moreno V … +12 more , Calvo A, Thistlethwaite F, Plummer R, Steinbach D, Loffredo J, Akapeme S, Jonathan D, Philip V, Girvin A, Hampras S, Hellemans P, Bulat I
Cancer Immunol Immunother · 2026 Jun · PMID 42313189 · Publisher ↗
PURPOSE: Pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous cetrelimab were assessed in Parts (P)3 and 4 of the phase I LUC1001 study in patients with advanced/refractory solid tumors who progressed...
PURPOSE: Pharmacokinetics, pharmacodynamics, safety, and efficacy of subcutaneous cetrelimab were assessed in Parts (P)3 and 4 of the phase I LUC1001 study in patients with advanced/refractory solid tumors who progressed on or wereineligible for standard treatment and had no prior PD-1/PD-L1/PD-L2 treatment. METHODS: In P3, low-concentration cetrelimab (30 mg/mL) was administered subcutaneously at 600 mg with a 6-week interval between doses 1 and 2, then every 3 weeks (Q3W). Based on P3 pharmacokinetic and safety findings, high-concentration cetrelimab (150 mg/mL) was administered subcutaneously at a 900 mg loading dose followed by 600 mg Q3W in P4. RESULTS: Among 30 enrolled patients (P3, n = 11; P4, n = 19), median age was 54.5y; 76.7% received ≥ 3 prior lines of therapy. Median duration of treatment was 2.1mo. Treatment-related adverse events (AEs) occurred in 70% of patients, including 23.3% with grade ≥ 3 treatment-related AEs and 30.0% immune-related AEs; no treatment-related serious AEs or systemic infusion-related reactions occurred. After 3.7mo median follow-up, 2 patients (6.7%) achieved durable responses and 4 patients (13.3%) had stable disease for ≥ 24 weeks. Pharmacokinetic data showed that adding a 900 mg loading dose to the 600 mg Q3W subcutaneous regimen shortened the time to reach target recommended phase 2 dose (RP2D) exposures, making it a suitable intravenous alternative. Maximum PD-1 receptor occupancy was achieved with both formulations. Anti-cetrelimab antibodies were detected in 4 patients (13.3%); none were neutralizing. CONCLUSIONS: RP2D of subcutaneous cetrelimab was established as a loading dose of 900 mg followed by 600 mg Q3W. Subcutaneous cetrelimab demonstrated characteristics consistent with prior characterization of intravenous cetrelimab. Trial registration NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016-002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017.
Impact of PD-1Tim-3CD8 T cells in pretreatment tumors on chemotherapy responses in esophageal cancer.
Sumimoto T, Yamamoto K, Saito T … +9 more , Urakawa S, Takeoka T, Makino T, Kurokawa Y, Kawashima A, Ueyama A, Eguchi H, Doki Y, Wada H
Cancer Immunol Immunother · 2026 Jun · PMID 42313187 · Publisher ↗
While chemotherapy has traditionally been recognized for its direct cytotoxic effects on cancer cells, increasing attention has been directed towards its capability to modulate tumor immune mechanisms. However, the major...
While chemotherapy has traditionally been recognized for its direct cytotoxic effects on cancer cells, increasing attention has been directed towards its capability to modulate tumor immune mechanisms. However, the majority of studies have focused on the quantitative assessment of tumor-infiltrating lymphocytes (TILs), without evaluating their functional status. Therefore, the present study investigated the pre-therapeutic exhaustion status of TILs and its impact on the efficacy of neoadjuvant chemotherapy (NAC) in patients with esophageal squamous cell carcinoma (ESCC). TILs were isolated from 60 endoscopic biopsy samples from ESCC patients before NAC. The proportion of CD8 TILs co-expressing PD-1 and Tim-3 was evaluated using flow cytometry. Their functional status was assessed by examining the expression of exhaustion markers (TOX, LAG-3, CD39), cytotoxic molecules (granzyme B, perforin), and cytokines (IFN-γ, TNF-α). A cytotoxic assay was also performed to evaluate their direct killing capacity against anti-CD3scFv BALL-1 cells. A high proportion of PD-1Tim-3CD8 TILs was significantly associated with a poor pathological response to NAC (p = 0.027) and was identified as an independent predictor of poor response in multivariate analysis (odds ratio = 4.1, 95% confidence interval = 1.1-14.7, p = 0.032). A functional analysis revealed that PD-1Tim-3CD8 TILs expressed high levels of exhaustion markers and low levels of cytotoxic molecules and cytokines and also exhibited impaired cytotoxic function. The proportion of PD-1Tim-3CD8 TILs decreased after NAC in responders. These results suggest the potential of a high proportion of PD-1Tim-3CD8 TILs in the pre-treatment tumor microenvironment as a useful predictor of a poor NAC response in ESCC patients.
Bintrafusp alfa for patients with recurrent or metastatic olfactory neuroblastoma.
London NR, Bracken-Clarke D, Xue E … +11 more , Brownell I, Mydlarz WK, Turkbey EB, Cordes LM, Marté JL, Rooper LM, Shah SB, Manu M, Sargi ZB, Gulley JL, Floudas CS
Cancer Immunol Immunother · 2026 Jun · PMID 42307670 · Publisher ↗
BACKGROUND: There is no established treatment for patients with recurrent/metastatic (R/M) olfactory neuroblastoma (ONB), a rare sinonasal tumor. We conducted the first immunotherapy clinical trial (NCT05012098) in patie...
BACKGROUND: There is no established treatment for patients with recurrent/metastatic (R/M) olfactory neuroblastoma (ONB), a rare sinonasal tumor. We conducted the first immunotherapy clinical trial (NCT05012098) in patients with R/M ONB, to evaluate the activity of the bifunctional TGF-β "trap"/anti-PD-L1 fusion protein bintrafusp alfa (BA). METHODS: Patients received BA (1200 mg, intravenously) every 2 weeks. Primary endpoint was overall response rate (ORR); secondary objectives included safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Between June 2022 and June 2023, 11 patients received treatment (Cohort 1, no prior immunotherapy, n=9; Cohort 2, prior immunotherapy received, n=2); enrollment was stopped due to BA development discontinuation. No objective responses were observed. In Cohort 1, 4 patients (of 8 evaluable, 50%) had stable disease (SD), three confirmed and long lasting; median PFS was 3.7 months, median OS was not reached; and one of SD patients had a complete metabolic response on Ga-DOTATATE imaging. In Cohort 2, 1 patient had SD; median PFS was 3 months, and median OS was 6.8 months. Grade 3/4 treatment-related adverse events occurred in 3 patients (immune-mediated diabetes, esophageal hemorrhage, anemia, epistaxis). CONCLUSIONS: Although the primary endpoint was not met, BA showed a manageable safety profile and a subset of patients derived clinical benefit with prolonged stable disease, including one patient with a complete metabolic response. This first clinical trial of systemic therapy in R/M ONB serves as proof of clinical trials feasibility in this setting and supports further investigation of combinatorial immunotherapy strategies in this patient population. Trial registration ClinicalTrials.gov Identifier: NCT05012098, https://clinicaltrials.gov/ct2/show/NCT05012098. Registered 18 August 2021.
CXCL9/SPP1-polarized tumor-associated macrophages exert dual roles in regulating anti-tumor immunity in lung adenocarcinoma.
Liu H, Wang L, Li C … +6 more , Li D, Meng L, Zheng G, Ren J, Shang L, Bao Y
Cancer Immunol Immunother · 2026 Jun · PMID 42301510 · Publisher ↗
BACKGROUND: CS polarity, the mutually exclusive expression of CXCL9 and SPP1, is a key feature of tumor-associated macrophages (TAMs) in the lung adenocarcinoma (LUAD) microenvironment. The mechanisms and impact of CS po...
BACKGROUND: CS polarity, the mutually exclusive expression of CXCL9 and SPP1, is a key feature of tumor-associated macrophages (TAMs) in the lung adenocarcinoma (LUAD) microenvironment. The mechanisms and impact of CS polarity on tumor progression remain incompletely understood. The study aims to define the molecular basis of CS polarity and its role in LUAD progression to inform new immunotherapies. METHODS: Single-cell RNA sequencing was used to characterize TAM subsets within the LUAD microenvironment, with survival analysis assessing their prognostic values and CellChat mapping cell-cell communication. In the functional validation section, a CS polarization regulation model of THP-1 cells was established. The Transwell co-culture system was utilized to evaluate its effects on the malignant behaviors of LUAD cells. CCK-8 assay, colony formation assay and cell migration assay were performed to detect cell proliferation and metastatic capacities. Flow cytometry was applied to determine the polarized phenotypes of TAMs (CD86⁺/CD163⁺). Dual-luciferase reporter assay was conducted to verify the direct transcriptional regulation of HPGDS promoter by MEF2C. Western blot, immunocytochemistry and qRT-PCR were adopted to analyze the activity of key signaling pathways. Furthermore, the above findings were further validated in vivo using a subcutaneous transplantation tumor model in nude mice. RESULTS: Five functionally distinct TAM subsets were identified. SPP1⁻CXCL9 TAMs were enriched in immune-activation pathways and strongly associated with favorable LUAD prognosis, whereas SPP1⁺CXCL9 TAMs participated in immune suppression and tumor-promoting processes, correlating with poor outcome. In vitro, increasing the CXCL9/SPP1 ratio synergistically promoted macrophages toward an M1 phenotype and suppressed LUAD cell proliferation, migration and invasion. In addition, CS polarity reversal further promoted MEF2C nuclear translocation and HPGDS transcription by activating the p38/MAPK signaling axis. Dual-luciferase reporter assays directly confirmed that MEF2C activated HPGDS transcription via specifically binding to its promoter, which served as a critical molecular event that induced phenotypic switching of TAMs and triggered their antitumor functions. In vivo experiments using the subcutaneous transplantation tumor model in nude mice further verified that combined treatment with KO-SPP1 and OE-CXCL9 markedly inhibited tumor growth and facilitated the polarization of intratumoral macrophages toward an antitumor phenotype, which was highly consistent with the in vitro findings. CONCLUSION: CS polarity modulates TAM polarization and their anti-tumor function through the p38/MAPK-MEF2C-HPGDS axis, offering theoretical foundation and potential targets for macrophage reprogramming-based LUAD immunotherapy.
BAP1 loss impairs IFN-γ signaling and enhances NK cell-mediated cytotoxicity in myeloid leukemia.
Badami C, Islamagic E, Blomén L … +5 more , Svensson F, Kathirkamanathan T, Hellstrand K, Bernson E, Thorén FB
Cancer Immunol Immunother · 2026 Jun · PMID 42295372 · Full text
Natural killer (NK) cells recognize and eliminate malignant cells through multiple receptor-ligand interactions. To uncover genetic determinants of the susceptibility of myeloid leukemia cells to NK cell cytotoxicity, we...
Natural killer (NK) cells recognize and eliminate malignant cells through multiple receptor-ligand interactions. To uncover genetic determinants of the susceptibility of myeloid leukemia cells to NK cell cytotoxicity, we analyzed several genome-wide CRISPR screens. Among recurrent hits, the BRCA1-associated protein 1 (BAP1) gene emerged as a key factor protecting K562 leukemic cells from NK cell-mediated killing. Using BAP1 knockout (KO) models, we found that loss of BAP1 alone did not alter NK cell sensitivity. However, upon interferon-γ (IFN-γ) stimulation, BAP1 KO K562 cells exhibited reduced HLA class I induction, triggered enhanced NK cell degranulation, and showed increased sensitivity to NK cell-mediated cytotoxicity compared with wild-type cells. Further experiments revealed that BAP1-deficient cells displayed reduced expression of the IFN-γ receptor 1 (IFN-γ-R1). BAP1 knockdown across multiple myeloid leukemia cell lines selectively decreased HLA-E and IFN-γ-R1 expression in ASXL1-mutant backgrounds. These findings suggest that BAP1 may contribute to the regulation of IFN-γ responsiveness and immune evasion in myeloid leukemia.
Real-world outcomes of ipilimumab plus nivolumab in esophageal squamous cell carcinoma: a multi-institutional large cohort study.
Hara S, Makino T, Nakai S … +14 more , Momose K, Yamashita K, Tanaka K, Satoh T, Sugimura K, Kawabata R, Takeno A, Motoori M, Yamasaki M, Miyata H, Kimura Y, Yasuda T, Eguchi H, Doki Y
Cancer Immunol Immunother · 2026 Jun · PMID 42289036 · Publisher ↗
BACKGROUND: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO + IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real...
BACKGROUND: Combination immune checkpoint inhibition with ipilimumab plus nivolumab (NIVO + IPI) has shown promising efficacy in advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate648 trial. However, real-world evidence regarding its safety, efficacy as first-line therapy, and host-related biomarkers relevant to immunotherapy remains limited. METHODS: This multicenter retrospective study evaluated a large cohort of 111 patients with unresectable advanced or recurrent ESCC who received first-line NIVO + IPI therapy. Treatment response, treatment-related adverse events, and prognostic factors were analyzed. RESULTS: The objective response and disease control rates in cases with target lesions were 44.0% and 70.7%, respectively. Treatment-related adverse events ≥ Grade 2 occurred in 58 (52.3%) patients, including one Grade 4 event (type 1 diabetes) and two Grade 5 events (biliary infection and myocarditis). The median overall survival (OS) and progression-free survival were 22 months (95% confidence interval [CI]: 13-not reached) and 5 months (95% CI 3-8), respectively. OS was significantly affected by lymph node metastasis in unresectable advanced disease and by liver metastasis in recurrent disease. Multivariate analysis of OS identified the C-reactive protein-to-albumin ratio (CAR), a marker of host immune-inflammatory status, as the only independent prognostic parameter (hazard ratio = 2.99, 95% CI 1.35-6.63, P = 0.0071). CONCLUSIONS: In this large real-world cohort, first-line NIVO + IPI therapy demonstrated meaningful clinical activity and an acceptable safety profile in advanced ESCC. Treatment outcomes varied according to metastatic patterns, suggesting an influence of organ-specific immune microenvironments, and CAR emerged as a simple and robust prognostic biomarker. These findings support the real-world applicability of dual immune checkpoint blockade and highlight the importance of host immune context in patient selection.
Surufatinib plus toripalimab for patients with advanced solid tumors and disease progression after prior immunotherapy: an open-label multi-cohort phase 2 trial.
Zhang P, Lu M, Song L … +12 more , Zhang Y, Chen Z, Wu C, Li Z, Zhang X, Xu Q, Zhou J, Shi H, Tan P, Fan S, Su W, Shen L
Cancer Immunol Immunother · 2026 Jun · PMID 42287432 · Publisher ↗
BACKGROUND: Immune checkpoint inhibitor (ICI) plus an anti-angiogenic agent has shown antitumor activity in patients whose disease had progressed on a prior ICI but further evidence across tumor types is needed. METHODS:...
BACKGROUND: Immune checkpoint inhibitor (ICI) plus an anti-angiogenic agent has shown antitumor activity in patients whose disease had progressed on a prior ICI but further evidence across tumor types is needed. METHODS: This phase 2 trial evaluated the efficacy and safety of surufatinib (anti-angiogenic multi-tyrosine-kinase inhibitor, 250 mg orally, once daily) plus toripalimab (programmed-death-1 [PD-1] inhibitor, 240 mg intravenously, once every three weeks) in adult patients with advanced solid tumors and progression on a PD-1/programmed death ligand 1 inhibitor. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: A total of 28 patients were enrolled and received treatment. Two of 27 evaluable patients achieved partial response, for an ORR of 7.4% (95% CI: 0.9-24.3); the disease control rate was 66.7% (95% CI: 46.0-83.5). Median progression-free survival was 3.9 months (95% CI: 1.4-4.2) and overall survival was 13.0 months (95% CI: 8.6-21.6; median follow-up: 20.9 months). Efficacy findings were consistent when assessed per immune-related RECIST. Eleven (39.3%) patients experienced grade ≥ 3 treatment-related adverse events (TRAEs), most frequently increased blood pressure (n = 3, 10.7%) and liver damage (n = 2, 7.1%). TRAEs led to surufatinib discontinuation in two (7.1%) patients. There were no treatment-related deaths. CONCLUSIONS: ICI-based combination rechallenge with surufatinib-toripalimab conferred signal-generating activity in patients with advanced solid tumors, with a manageable safety profile. Studies in larger populations are warranted.
Neoadjuvant immunochemotherapy followed by definitive radiotherapy in locally advanced head and neck squamous cell carcinoma: two-year survival outcomes.
Xu Y, Meng Y, Gui L … +10 more , Zhang Y, Wu R, Chen X, Huang X, Wang K, Qu Y, Ma Y, Zhang J, Wang J, Yi J
Cancer Immunol Immunother · 2026 Jun · PMID 42283875 · Publisher ↗
PURPOSE: To evaluate the clinical response, survival outcomes, and organ-preservation potential in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients treated with neoadjuvant immunochemotherapy (N...
PURPOSE: To evaluate the clinical response, survival outcomes, and organ-preservation potential in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients treated with neoadjuvant immunochemotherapy (NIC) followed by definitive radiotherapy (DRT). METHODS: We retrospectively reviewed patients with stage III-IVb HNSCC treated with NIC followed by DRT between 2021 and 2023. Tumor response was assessed after NIC and after completion of DRT according to RECIST 1.1. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Toxicities were graded according to CTCAE 5.0 criteria. RESULTS: A total of 74 patients were included, with hypopharyngeal tumors accounting for 47.3%. All patients completed at least two cycles of NIC. After NIC, the objective response rate was 89.2%, with clinical complete response (cCR) and clinical partial response (cPR) rates of 1.4% and 87.8%, respectively. After DRT, the corresponding rates shifted to 17.6% and 77.0%, respectively. With a median follow-up of 24 months (range: 5-38 months), the estimated 2-year OS and PFS rates were 83.2% and 61.7%. Among patients with laryngeal or hypopharyngeal carcinoma, the larynx-preservation rate was 95.2% and the 2-year larynx-preservation OS reached 73.6%. NIC-related adverse events were predominantly grades 1-3 (90.0%). CONCLUSION: NIC followed by DRT was associated with high response rates, encouraging survival outcomes, and manageable toxicities in this retrospective cohort. While organ-preservation rates are promising, the modest PFS highlights the need for further investigation in larger or selective cohorts.
Beyond radiation: immunological potentials of boron neutron capture therapy.
Abulimiti M, Sugawara Y, Li Y … +2 more , Sakurai H, Matsumoto Y
Cancer Immunol Immunother · 2026 Jun · PMID 42283859 · Publisher ↗
Boron neutron capture therapy (BNCT) is a targeted radiotherapeutic modality that employs boron-10 (B) to capture thermal neutrons, thereby releasing high-linear energy transfer α-particles and lithium ions that selectiv...
Boron neutron capture therapy (BNCT) is a targeted radiotherapeutic modality that employs boron-10 (B) to capture thermal neutrons, thereby releasing high-linear energy transfer α-particles and lithium ions that selectively eradicate tumor cells while sparing the surrounding normal tissues. Immune checkpoint inhibitors (ICIs), including inhibitors of PD-1/PD-L1 and CTLA-4, enhance antitumor immunity by alleviating immunosuppression within the tumor microenvironment. As immunotherapy continues to expand across multiple tumor types and becomes integral to systemic cancer treatment, attention has increasingly focused on combining systemic immunomodulation with localized therapies. BNCT functions primarily as a local therapeutic approach, whereas ICIs elicit systemic immune activation. Whether the two modalities can produce synergistic therapeutic effects remains an important question.In this narrative review, we summarize current mechanistic insights, preclinical and clinical developments, and ongoing challenges associated with the combination of BNCT and ICIs, highlighting the potential of this strategy to achieve durable, synergistic antitumor responses.
Donor-specific toxicity of copanlisib identified using immune-humanized mice.
Becker RE, Résiliac J, Gabrielson KL … +2 more , Liu Z, Howard KE
Cancer Immunol Immunother · 2026 Jun · PMID 42283858 · Publisher ↗
Copanlisib is a pan-phosphoinositide-3-kinase-inhibitor originally indicated for adult patients with relapsed follicular lymphoma who had received at least two prior systemic therapies. At the time this study was conduct...
Copanlisib is a pan-phosphoinositide-3-kinase-inhibitor originally indicated for adult patients with relapsed follicular lymphoma who had received at least two prior systemic therapies. At the time this study was conducted, it was approved for use by the FDA and was being evaluated in clinical trials in combination therapy with checkpoint inhibitors for a range of cancers.Prior to conducting studies with the combination of copanlisib and checkpoint inhibitors, we conducted a pilot study to determine route of administration, identify an appropriate dose, and assess the effects of copanlisib in bone marrow-liver-thymus (BLT) immune-humanized mice. We tested three doses of copanlisib via two routes of administration in humanized mice produced from three unique donors and evaluated tissue-based toxicity via histopathology and immune changes with flow cytometry.Histopathology showed no significant correlation in pathological findings based on copanlisib dose or administration route. However, analysis of the histopathology by donor revealed clear differences, with one donor showing significant pathology, regardless of treatment dose or route, while the other two donors showed little to no adverse treatment effects. Flow cytometric analysis showed the affected donor had significantly more activated T-cells present in the bone marrow regardless of dose or route of administration.Although our findings represent only one of three donors used in immune-humanized mice, this study suggests that some immune modulating therapeutic toxicity could be associated with specific genetic factors from individual patients rather than being dose related.
Correction to: Bevacizumab reduces PD-L1 Not PD-1 inhibitor-associated pneumonitis in non-small cell lung cancer patients.
Wang L, Xu Y, Zhao Y … +2 more , Xia B, Zhu L
Cancer Immunol Immunother · 2026 Jun · PMID 42268402 · Full text
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Low-dose IL-2 therapy for immune-related adverse events via Tfh/Treg balance modulation: a prospective cohort and murine model study.
Wang Y, Zhang Z, Li Y … +6 more , Cheng Y, Wang M, Liu Y, Li H, Peng Z, He J
Cancer Immunol Immunother · 2026 Jun · PMID 42262537 · Publisher ↗
BACKGROUND: Immune-related adverse events (irAEs) are associated with anti-PD-1/PD-L1 therapy in gastrointestinal cancers. Altered phenotypes and frequencies of T cell subsets play a critical role in irAEs. This study ch...
BACKGROUND: Immune-related adverse events (irAEs) are associated with anti-PD-1/PD-L1 therapy in gastrointestinal cancers. Altered phenotypes and frequencies of T cell subsets play a critical role in irAEs. This study characterized the Tfh/Treg balance in irAEs patients and assessed the efficacy of LDIL-2 therapy in mouse models. METHODS: A prospective study evaluating the immunological characteristics of 26 gastrointestinal cancer patients through both cellular and transcriptomic analyses before and after anti-PD-1/PD-L1 therapy was performed. Patients were categorized into two groups: the AE group (patients who developed irAEs during the follow-up period) and the NAE group (patients who did not). Meanwhile, MRL/MpJ-Fas mice, a lupus mouse model, and tumor-bearing C57BL/6 J mice were used to evaluate the efficacy of LDIL-2 in treating anti-PD-L1 induced irAEs and its impact on antitumor effectiveness. RESULTS: Our study discovered that in AE patients, Tfh-related genes were significantly upregulated during the early stages of anti-PD-1/PD-L1 therapy (IL-21: p < 0.01; PDCD1: p < 0.05), whereas the upregulation of Treg-related genes was less pronounced compared to Tfh-related genes. This distinction was not observed in NAE patients. Flow cytometry results further confirmed a substantial increase in the Tfh/Treg ratio in AE patients during the early stages of therapy (p < 0.001), a phenomenon absent in NAE patients. In MRL/MpJ-Fas mice, anti-PD-L1 therapy induced a shift in the Tfh/Treg ratio, along with severe organ inflammatory lesions and elevated anti-dsDNA antibody levels. In contrast, LDIL-2 treated mice maintained a balanced Tfh/Treg ratio, exhibiting significantly fewer organ inflammatory lesions and reduced anti-dsDNA production. Furthermore, in tumor-bearing mice, LDIL-2 did not impair the antitumor efficacy of anti-PD-L1 therapy. CONCLUSIONS: Our study underscores the importance of Tfh/Treg balance in the development of irAEs and demonstrates the potential of LDIL-2 as a therapeutic option for irAEs, providing a promising alternative to traditional immunosuppressive therapies for managing irAEs.
Optimizing the clinical assessment of pseudoprogression in patients with solid tumors treated with checkpoint inhibitors: a systematic literature review and meta-analysis of associated features.
Fountoukidis G, Tina E, Göthlin-Eremo A … +2 more , Ullenhag G, Valachis A
Cancer Immunol Immunother · 2026 Jun · PMID 42257909 · Full text
BACKGROUND: Pseudoprogression is an atypical response pattern observed during treatment with immune checkpoint inhibitors (CPIs) that can complicate clinical decision-making. It is characterized by initial radiologic pro...
BACKGROUND: Pseudoprogression is an atypical response pattern observed during treatment with immune checkpoint inhibitors (CPIs) that can complicate clinical decision-making. It is characterized by initial radiologic progression followed by subsequent tumor regression or stabilization, with confirmation requiring repeat imaging. We aimed to characterize the clinical and imaging features of confirmed pseudoprogression in solid tumors treated with CPIs using pooled study data. METHODS: We systematically searched MEDLINE, Embase, and Web of Science through December 2025. Prospective and retrospective cohort studies and randomized trials reporting confirmed pseudoprogression during CPI therapy were eligible. Two independent reviewers performed study selection and data extraction using predefined criteria. Study quality was assessed using the Joanna Briggs Institute checklist. Pooled analyses were conducted with RevMan and Stata. Outcomes included time to initial radiologic progression, magnitude of tumor burden increase, occurrence of new lesions, changes in nontarget lesions, and subsequent objective response. RESULTS: Thirteen retrospective studies were included; most applied iRECIST criteria. The pooled median time to initial progression was 2.52 months (95% CI, 1.54-3.51). Mean tumor burden increase was 33.0% (95% CI, 22.7-43.3), and new lesions occurred in 35.3% of cases. Tumor burden increases > 100% were rare (3.9%). Despite initial progression, 41.8% subsequently achieved partial response and 6.4% complete response without therapy change. Median time to best response was 2.79 months (95% CI, 0.62-7.20). CONCLUSIONS: Pseudoprogression typically occurs early during CPI therapy and is associated with modest tumor growth. Marked tumor increases are uncommon and may help distinguish true progression. Careful clinical and radiologic assessment remains essential.
Immune-cold NSCLC tumors harbor tumor-associated macrophages with elevated expression of immunoglobulin genes.
Haug M, Pettersen HS, Børset M … +4 more , Kildahl-Andersen A, Wahl SGF, Flatberg A, Tøndell A
Cancer Immunol Immunother · 2026 Jun · PMID 42251193 · Publisher ↗
In the non-small cell lung cancer (NSCLC) tumor microenvironment (TME), tumor cells mediate inhibitory signals to key immune cells, promoting an immunosuppressive environment that facilitates tumor immune evasion. CD8 + ...
In the non-small cell lung cancer (NSCLC) tumor microenvironment (TME), tumor cells mediate inhibitory signals to key immune cells, promoting an immunosuppressive environment that facilitates tumor immune evasion. CD8 + cytotoxic T lymphocytes are central mediators of antitumor immunity, and tumors can be classified by immunohistochemistry (IHC) as immune-hot or immune-cold based on the abundance of tumor-infiltrating lymphocytes (TILs). Although cancer immunotherapy can boost lymphocyte functions and improve progression-free survival in patients with advanced NSCLC, only a minority of patients experience a durable clinical benefit. Tumor-associated macrophages (TAMs) are key immunoregulatory cells in the NSCLC microenvironment and capable of generating potent immunosuppressive signals. However, their functional roles in immune-hot versus immune-cold tumors remain poorly understood. In this study, we compared the transcriptional programs of TAMs from NSCLC patients with immune-hot or immune-cold tumors. We classified 11 surgically resected NSCLC tumors as immune‑hot or immune‑cold based on quantitative immunohistochemistry of CD4⁺ and CD8⁺ tumor‑infiltrating lymphocytes. TAMs were isolated from tumor and adjacent healthy tissue by fluorescence-activated cell sorting (FACS), followed by bulk RNA sequencing and differential gene expression analysis. TAMs from immune‑cold tumors exhibited a striking upregulation of genes involved in immunoglobulin-mediated immune responses. Additionally, these TAMs demonstrated increased expression of genes involved in extracellular matrix organization, including matrix metalloproteinases and collagen‑associated genes, suggesting enhanced matrix remodeling activity. These findings highlight TAMs' potential contribution to immunosuppression, stromal remodeling, and impaired lymphocyte infiltration. The TAM-mediated pathways identified here may represent actionable targets for future immunotherapeutic strategies aimed at reshaping the tumor microenvironment.
Explainable AI reveals squamous histology and U-shaped PD-L1 patterns as primary subgroup predictors of neoadjuvant and perioperative immunotherapy benefit in NSCLC: a machine learning analysis.
Shen F, Zhu Z, Liu J … +1 more , Li F
Cancer Immunol Immunother · 2026 Jun · PMID 42249154 · Publisher ↗
BACKGROUND: The introduction of neoadjuvant and perioperative immunotherapy has broadened treatment options for resectable non-small cell lung cancer (NSCLC). However, clinical benefit varies across subpopulations, and s...
BACKGROUND: The introduction of neoadjuvant and perioperative immunotherapy has broadened treatment options for resectable non-small cell lung cancer (NSCLC). However, clinical benefit varies across subpopulations, and standard linear models cannot fully capture the complex feature interactions and trial-level differences found in aggregate data. METHODS: We applied an integrated framework combining multilevel meta-regression with an inverse-variance weighted eXtreme Gradient Boosting (XGBoost) algorithm. SHapley Additive exPlanations (SHAP) were used to interpret the model and identify efficacy variance drivers across seven randomized controlled trials. RESULTS: Multilevel meta-regression demonstrated that event-free survival (EFS) benefit correlated positively with PD-L1 expression, peaking in the 50% subgroup (adjusted HR = 0.44, 95% CI: 0.33--0.57). XGBoost-SHAP analysis revealed trial-level variance as the dominant driver of heterogeneity. Among subgroup-level clinical covariates, a non-linear U-shaped PD-L1 predictive pattern (<1% and 50%), squamous cell carcinoma (SCC) histology (HR = 0.53, 95% CI: 0.43--0.65), and smoking history emerged as primary predictors. Synthesizing these signatures into a hypothesis-generating subgroup stratification framework indicated that SCC and PD-L1-negative (<1%) non-squamous cohorts benefit from continuous perioperative blockade. Conversely, exploratory analyses suggested that PD-L1-positive (1%) non-squamous tumors achieved maximal observed benefit from exclusively neoadjuvant regimens (HR = 0.50). CONCLUSIONS: Our results suggest that for PD-L1-positive non-squamous cases, the added benefit of extended adjuvant therapy may be limited. However, given our reliance on aggregate data and trial-level imbalances, these findings remain hypothesis-generating and should not alter current clinical practice. Rather, they offer an exploratory framework to inform patient selection for future de-escalation trials.
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