Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Dual targeting of CD155 augments the antitumor efficacy of ROR1-CAR-T cells in ovarian cancer.
Ye Y, Liu T, Cheng C … +4 more , Wang H, Shen J, He X, Xu S
Cancer Immunol Immunother · 2026 Jan · PMID 41591545 · Full text
BACKGROUND: Exploring novel therapeutic targets and developing targeted therapies constitute an urgent clinical need for improving the prognosis of ovarian cancer (OC), particularly among patients with advanced stages. C...
BACKGROUND: Exploring novel therapeutic targets and developing targeted therapies constitute an urgent clinical need for improving the prognosis of ovarian cancer (OC), particularly among patients with advanced stages. Currently, chimeric antigen receptor T (CAR-T) cell therapy has been demonstrated to have a remarkable therapeutic effect in hematological malignancies, while its application remains limited in OC due to the absence of appropriate target molecules and the complex immunosuppressive tumor microenvironment (TME). Poliovirus receptor (PVR, CD155) has been the subject of extensive research in the field of regulatory molecules within the immune microenvironment. However, there has been a paucity of research investigating its role in OC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is barely expressed in normal tissues but widely expressed in tumor tissues, making it a promising target for CAR-T therapy. Nevertheless, the potential effectiveness of CAR-T cell targeting ROR1 in OC remains unknown. Therefore, the purpose of this study is twofold: The primary objective of this study is to investigate the potential efficacy of single-target ROR1-CAR-T cells on OC. The secondary objective is to examine the feasibility of CD155 as an immunotherapy target for OC and to determine whether combined targeting of CD155 can enhance the function of ROR1-CAR-T cells in OC. METHOD: ROR1 and CD155 expression were detected via flow cytometry analysis. In vitro experiments were conducted to explore the regulatory effect of CD155 on OC proliferation, invasion, angiogenesis, and T cell function. ROR1-CAR, CD155-CAR, and ROR1/CD155 bispecific CAR constructs were designed and synthesized. Then, they were introduced into T cells using lentiviral particles to generate CAR-T cells. We subsequently validated the synergistic effects of CD155 in ROR1/CD155 bispecific CAR-T cells based on cytotoxic efficacy, activation, exhaustion, and differentiation status. RESULTS: ROR1-CAR-T cells exhibited tumoricidal activity in OC, but elevated tonic signaling was observed, resulting in rapid depletion. CD155 constitutes an ideal therapeutic target in OC: firstly, ubiquitous CD155 expression in OC cell lines. Secondly, CD155 promotes tumor proliferation, migration, and angiogenesis in OC cell lines, acting as an oncogenic driver. Thirdly, CD155 impairs T cell function and accelerates their depletion, contributing to an immunosuppressive TME. The bispecific CAR-T combined targeting CD155 and ROR1 demonstrated superior cytotoxicity compared to single-target ROR1-CAR-T or CD155-CAR-T. Co-targeting CD155 significantly attenuated tonic signaling and delayed CAR-T cell exhaustion. CONCLUSION: CD155 emerges as a promising therapeutic target for CAR-T therapy in OC. The bispecific CAR-T construct that co-targets CD155 and ROR1 demonstrates superior and durable tumoricidal activity, offering new perspectives on OC targeted therapy.
Dynamic circulating biomarkers for predicting adverse events in PRaG therapy: a pooled analysis and model construction from PRaG series clinical trials.
Chen WW, Li SC, Yin Q … +6 more , Xu ML, Zhang JJ, Zhao XR, Xing PF, Kong YH, Zhang LY
Cancer Immunol Immunother · 2026 Jan · PMID 41591538 · Full text
BACKGROUND: PRaG therapy (PD-1/PD-L1 inhibitor combined with Radiotherapy and Granulocyte-macrophage colony-stimulating factor) has emerged as a novel, intensive, and promising combined regimen for advanced solid tumors....
BACKGROUND: PRaG therapy (PD-1/PD-L1 inhibitor combined with Radiotherapy and Granulocyte-macrophage colony-stimulating factor) has emerged as a novel, intensive, and promising combined regimen for advanced solid tumors. It has been adopted as a National Health Commission-promoted technology in China, demonstrating significant survival benefits. This study aims to delineate the adverse events (AEs) profile of PRaG therapy and evaluate the predictive value of dynamic circulating biomarkers for moderate-to-severe AEs. METHODS: 203 patients with advanced solid tumors initiating PRaG therapy were prospectively enrolled and stratified by maximum treatment-related AEs severity (AE ≤ Grade1 vs. AE ≥ Grade2). The predictive value was assessed by comparing circulating indicators at baseline and one cycle prior to AEs onset (pre-AEs cycle). A predictive model was then constructed and subjected to independent internal validation. RESULTS: Patients experiencing AE ≥ Grade2 exhibited significantly superior survival outcomes. Multivariate analysis of dynamic circulating indicators revealed that pre-AEs cycle levels of Interleukin-2 (IL-2, p = 0.004), CD4 + effector memory T cells (p = 0.001), CD8 + effector memory T cells (p = 0.012), and the CD4 + effector/CD8 + effector memory T-cell ratio (p < 0.001) were independent predictors for AE ≥ Grade2. Integrating these fine typing of circulating T lymphocyte subsets into the prediction model significantly enhanced performance (AUC increased from 0.685 to 0.867), with independent internal validation confirming model reliability (AUC = 0.913). CONCLUSION: This study successfully delineated the real-world safety profile of PRaG therapy and identified a distinct set of dynamic circulating biomarkers strongly associated with moderate-to-severe AEs. The established non-invasive prediction model offers an effective tool for clinical early warning and proactive management in PRaG patients.
Efficacy and safety of anti-LAG-3 IBI110 in combination with sintilimab and chemotherapy for advanced squamous non-small cell lung cancer: a randomized phase II study.
Wang Q, Xiong A, Mao C … +17 more , Wang W, Cui J, Fang J, Zhuang W, Yang K, Zuo W, Yang J, Ye L, Zhang Z, Sheng Z, Liu Z, Wang D, Du X, Yi T, Long S, Xu N, Zhou C
Cancer Immunol Immunother · 2026 Jan · PMID 41591537 · Full text
OBJECTIVE: To evaluate the efficacy and safety of the anti-lymphocyte activation gene-3 (LAG-3) antibody IBI110 in combination with sintilimab and chemotherapy in patients with advanced squamous non-small cell lung cance...
OBJECTIVE: To evaluate the efficacy and safety of the anti-lymphocyte activation gene-3 (LAG-3) antibody IBI110 in combination with sintilimab and chemotherapy in patients with advanced squamous non-small cell lung cancer (sqNSCLC). METHODS: In this multicenter, randomized, open-label, phase II study, 153 patients with previously untreated advanced sqNSCLC were randomly assigned at a 1:1:1 ratio to one of three groups: IBI110 200 mg plus sintilimab (200 mg) and chemotherapy (n = 51), IBI110 600 mg plus sintilimab and chemotherapy (n = 51), or sintilimab plus chemotherapy (standard-of-care, SOC, n = 51). The primary endpoints included the objective response rate (ORR), progression-free survival (PFS) and safety. LAG-3 expression in tumor tissue was detected by immunohistochemistry (IHC) to explore its correlation with treatment efficacy. RESULTS: While no statistically significant differences in ORR, PFS, or overall survival (OS) were observed across the three arms in the overall population, promising efficacy signals emerged in the LAG-3 expression ≥ 2% subgroup. In this subset, compared with the SOC regimen, the IBI110 200 mg regimen significantly improved the duration of response (DOR: 13.73 vs. 6.51 months, P = 0.037) and PFS (P = 0.0485). The safety results indicated that the IBI110 200 mg combination was manageable, with a higher incidence of grade ≥ 3 treatment-related adverse events (56.86% vs. 29.41%) primarily consisting of controllable hematological toxicities. CONCLUSION: The high-LAG-3 subgroup demonstrated enhanced efficacy following the addition of IBI110 to sintilimab and chemotherapy, despite the absence of improvement in the overall population with advanced sqNSCLC, supporting further investigations in biomarker-defined patients. TRIAL REGISTRATION: The current study has been registered with ClinicalTrial.gov (Identifier: NCT04085185).
Optimal genetic feeder cell-expanded and engineered NK cell products are composed of CD56 and CD56 NK cells.
van Hees EP, Pothast CR, Pool ES … +3 more , Falkenburg JHF, Melsen JE, Heemskerk MHM
Cancer Immunol Immunother · 2026 Jan · PMID 41591514 · Full text
Natural killer (NK) cells represent a promising source for off-the-shelf cellular therapies. Typically, NK cells are expanded with cytokines and K562 feeder cells expressing 4-1BBL and membrane-bound IL-21, which induce...
Natural killer (NK) cells represent a promising source for off-the-shelf cellular therapies. Typically, NK cells are expanded with cytokines and K562 feeder cells expressing 4-1BBL and membrane-bound IL-21, which induce a uniform and activated CD56 phenotype. However, the developmental origin of these cells remains unclear, arising either from CD56 NK cells through phenotypic plasticity or from functional maturation of the CD56 subset. In this study, we dissected the respective contributions of CD56 and CD56 NK cells to engineered NK cell products. NK cell populations were sorted, and their activation, expansion, phenotype, and functionality were assessed. We found that CD56 NK cells were initially critical for proliferation and feeder clearance, but after restimulation, they exhibited comparable cytotoxicity and expansion to CD56 NK cells. This was further highlighted by the ability of both subsets to mediate CAR- or TCR-driven cytotoxicity. Eventually, sorted and expanded NK cells acquire the same activated phenotype, but can be distinguished by CD16 expression, predominantly maintained by CD56 cells, resulting in superior antibody-dependent cellular cytotoxicity. Together these findings indicate that preselection of a single subset is redundant, and that bulk isolation enables optimal NK cell engineering by leveraging the complementary strengths of CD56 and CD56 NK cells.
Tumor-associated macrophages in head and neck carcinoma: clinicopathological correlations and implications for immunotherapy.
Evrard D, Beaufrère A, Dumont C … +12 more , Louërat S, Chaud A, Guyard A, Laouirem S, Albuquerque M, Tijeras-Raballand A, Couvelard A, Paradis V, Halimi C, Raymond É, Hourseau M, Faivre S
Cancer Immunol Immunother · 2026 Jan · PMID 41591510 · Full text
Tumor-associated macrophages (TAMs) and other PD-L1-expressing immune cells play a key role in head and neck squamous cell carcinoma (HNSCC). As PD-1 inhibitors have become standard therapy for recurrent/metastatic disea...
Tumor-associated macrophages (TAMs) and other PD-L1-expressing immune cells play a key role in head and neck squamous cell carcinoma (HNSCC). As PD-1 inhibitors have become standard therapy for recurrent/metastatic disease and are now used perioperatively in locally advanced resectable cases, understanding their impact on TAMs dynamics is critical. This study investigated the association between clinical features and TAMs prevalence in HNSCC, and their potential role in tumor progression and resistance to PD-1 blockade. Tumor samples from HNSCC patients were analyzed by simplex and multiplex immunohistochemistry, and fresh tumor slices were cultured ex vivo with PD-1 inhibitors. CD68 + and CD163 + macrophages and PD-L1 expression were quantified and correlated with clinical parameters. In a tissue microarray cohort of 96 patients, CD68 + and CD163 + macrophages were more abundant in oral and oropharyngeal tumors compared to laryngeal and hypopharyngeal carcinomas (p = 0.001 and p = 0.06, respectively). In 10% of cases, TAMs formed a barrier between tumor nests and immune infiltrates. Among nine patients with matched pre- and post-immunotherapy samples, TAMs density significantly increased post-treatment (p = 0.01 and p = 0.03), with CD163 + macrophages clustering at the tumor periphery in 78% of cases. Multiplex staining confirmed this spatial reorganization. Ex vivo exposure to PD-1 inhibitors reproduced the increase in TAMs. These results suggest that PD-1 blockade may foster M2-like macrophage accumulation, potentially contributing to immune evasion. This underscores the need for prospective studies and the development of macrophage-targeted strategies, particularly in the emerging context of perioperative immunotherapy in HNSCC.
A phase 2 study of orally administered live biotherapeutic salmonella-IL2 with FOLFIRINOX for stage IV pancreatic cancer.
Batist G, Kavan P, Augustin L … +4 more , Schottel J, Moradian J, Lee JT, Saltzman D
Cancer Immunol Immunother · 2026 Jan · PMID 41591505 · Full text
Salmonella-IL2 is an attenuated Salmonella Typhimurium strain carrying the human gene for IL-2. When orally administered in preclinical trials, the bacterium colonizes tumors and locally releases IL-2, triggering immunol...
Salmonella-IL2 is an attenuated Salmonella Typhimurium strain carrying the human gene for IL-2. When orally administered in preclinical trials, the bacterium colonizes tumors and locally releases IL-2, triggering immunologically-mediated tumor cell killing without untoward side effects. A non-randomized, phase 2 study evaluated the combination of Salmonella-IL2 with standard of care (SOC) chemotherapy where patients received Salmonella-IL2 plus FOLFIRINOX (FFX). Overall survival (OS), progression-free survival (PFS), safety, and biomarker data in each arm were studied. In total, 34 patients (30 in the trial, 4 via EAP) were enrolled: 26 received Salmonella-IL2 with FOLFIRINOX. Those patients who received more than five doses of Salmonella-IL2 with FOLFIRINOX (n = 20) had a mPFS of 15 months while the mOS was 20.3 months. Even though there were no complete responses, the partial response rate and the overall response rate was 70.0%. In addition, 41 serious adverse events were noted and attributed to SOC chemotherapy agents but none to Salmonella-IL2. Addition of Salmonella-IL2 to FOLFIRINOX is associated with increased mPFS and mOS when compared to previously reported outcomes with FOLFIRINOX alone in the literature. A multicenter, randomized, phase 3 trial is warranted. ClinicalTrials.gov identifier: NCT04589234.
Risk factors and outcomes for steroid-refractory immune-related hepatotoxicity in locally advanced and metastatic cancer.
Liu S, Zhang Y, Guan Y … +6 more , Xie H, Dong Y, Chang J, Xie Q, Wang B, Wang J
Cancer Immunol Immunother · 2026 Jan · PMID 41591499 · Full text
Immune-related hepatotoxicity (IRH) is one of the common immune-related adverse events caused by immune checkpoint inhibitors (ICIs). Some patients with steroid-refractory IRH (Ref-IRH) are potentially life-threatening....
Immune-related hepatotoxicity (IRH) is one of the common immune-related adverse events caused by immune checkpoint inhibitors (ICIs). Some patients with steroid-refractory IRH (Ref-IRH) are potentially life-threatening. This study was designed to determine the risk factors and outcomes for Ref-IRH. Locally advanced or metastatic cancer patients who developed steroid-responsive IRH (Res-IRH) or Ref-IRH were identified between December 1, 2019 and September 1, 2024. Patient characteristics, peripheral blood biomarkers, and cytokine levels were collected. In this cohort of 480 patients treated with immune checkpoint inhibitors, 35 patients (7.3%) developed IRH, including 12 with Res-IRH and 13 with Ref-IRH. Patients with Ref-IRH were more likely to be hepatocellular carcinoma (p = 0.035), receive ICIs plus targeted therapy (p = 0.046), and have higher CTCAE grades (p = 0.044) at diagnosis. Patients with Ref-IRH had lower platelet counts (p = 0.006), higher procalcitonin levels (p = 0.012), and higher IL-6 levels (p = 0.038). Univariate logistic regression analysis indicated that higher IL-6 at diagnosis was a potential risk factor for Ref-IRH (p = 0.019). All Ref-IRH patients were treated with immunosuppressive agents. The survival outcomes of Ref-IRH were comparable to those of Res-IRH. Patients with Ref-IRH were unlikely to quickly recover with a longer time from initial diagnosis of IRH to resolution to grade 1 (p = 0.002), from peak ALT (p = 0.007), AST (p = 0.011), and TBIL (p = 0.048) to resolution to grade 1, from initial diagnosis of IRH to use of prednisone ≤ 20 mg/day (p = 0.025), and prolonged hospital length of stay (p = 0.017). In conclusion, high IL-6 at diagnosis is a potential risk factor for the development of Ref-IRH. There was no significant difference in efficacy and survival between patients with Ref-IRH and Res-IRH, but much more time from the initial diagnosis of IRH to resolution to grade 1 and the use of immunosuppressive agents is needed for Ref-IRH patients.
Radiotherapy dose may not affect prognosis in ESCC patients receiving first-line chemoradiotherapy-immunotherapy: A multicenter retrospective study.
Wen J, Liu X, Xu Y … +10 more , Lin Z, Hou M, Gui Y, Cao J, Hou Q, Lv J, Wang L, Zhou W, Zeng Z, Shen W
Cancer Immunol Immunother · 2026 Jan · PMID 41591498 · Full text
BACKGROUND: Combined immunotherapy based on radiotherapy and chemotherapy is increasingly widely applied in clinical practice for patients with non-surgical treatment of esophageal cancer. However, radiotherapy doses in...
BACKGROUND: Combined immunotherapy based on radiotherapy and chemotherapy is increasingly widely applied in clinical practice for patients with non-surgical treatment of esophageal cancer. However, radiotherapy doses in triple combination therapy have not received much attention. Therefore, a retrospective, non-interventional, real-world study of patients with esophageal squamous cell carcinoma (ESCC) was conducted. The primary objective was to assess whether radiotherapy dose is a determining factor in the prognosis of ESCC patients in a triple therapy. METHODS: A total of 1283 ESCC patients receiving triple therapy were collected from 7 cancer centers in China between January 2019 and December 2022. Among them, 299 ESCC patients receiving the first-line triple therapy were eligible for enrollment. Due to different radiotherapy doses, patients were classified into a high-dose (HD) group at 60Gy and a low-dose (LD) group at 50.4Gy. Propensity Score Matching (PSM) analysis was conducted to compare and analyze differences in outcomes, toxicity, and failure patterns between the two groups. Further subgroup analysis was performed to identify the individual population. RESULTS: Of the 299 ESCC patients eligible for enrollment, 198 (66.2%) were in the HD group and 101 (33.8%) were in the LD group. After PSM, there were 93 patients in each group. The median follow-up time was 25.5 months (95CI: 18.6-32.4). The median overall survival (mOS) and median progression-free survival (mPFS) in the LD group were 31.3 months (95%CI: 16.5-46.2) and 17.0 months (95%CI: 15.1-19.0), respectively. The mOS and mPFS in the HD group were 28.5 months (95%CI: 16.1-40.9) and 20.6 months (95%CI: 13.5-27.8), respectively. There was no statistically significant difference between the HD group and the LD group (X = 0.057, 0.974, P = 0.811, 0.324). The disease control rates of LD and HD groups were 89.2% and 90.3% respectively, and the difference was not statistically significant (X = 0.059, P = 0.809). In the LD group, 35 cases (37.6%) had distant metastasis and 21 cases (22.6%) had local recurrence. In the HD group, 32 cases (34.4%) had distant metastasis and 14 cases (15.1%) had local recurrence. There were no statistically significant differences between the HD group and the LD group (X = 1.725, 0.210, P = 0.189, 0.647). CONCLUSION: Multicenter data from China showed that higher radiotherapy doses provide no survival benefit for ESCC patients receiving first-line triple therapy.
Metabolic syndrome and immune-related adverse events.
Lei K, Patel MJ, Liu J … +10 more , Rathod RA, von Itzstein MS, Fattah FJ, Mu-Mosley H, SoRelle JA, Park JY, Xie Y, Hughes AE, Kitzman H, Gerber DE
Cancer Immunol Immunother · 2026 Jan · PMID 41591497 · Full text
BACKGROUND: Years into the immune checkpoint inhibitor (ICI) era, immune-related adverse events (irAE) remain largely unpredictable. Prior studies have examined irAE associations with weight and metabolic diseases, yield...
BACKGROUND: Years into the immune checkpoint inhibitor (ICI) era, immune-related adverse events (irAE) remain largely unpredictable. Prior studies have examined irAE associations with weight and metabolic diseases, yielding mixed findings. We therefore analyzed these and other variables potentially associated with heightened inflammation and irAE development. METHODS: For ICI-treated individuals enrolled in a prospective institutional clinical and biospecimen registry, we collected demographic, clinical, laboratory, and residence data, pre-ICI serum cytokine levels, and irAE details. We calculated metabolic syndrome (MetS) and area deprivation index (ADI, a measure of neighborhood socioeconomic status), both of which have been associated with heightened inflammation. Patients were categorized as having MetS if they had ≥ 3 of 5 criteria at ICI initiation: hypertension, obesity, elevated HbA1c, low HDL, elevated triglycerides. Baseline serum cytokine/chemokine levels were determined using a multiplex platform. We analyzed associations across variables using logistic regression, Mann-Whitney U, and Cochran Armitage tests, accounting for multiple comparisons. RESULTS: Overall, 178 ICI-treated patients were included in the analysis, of whom 99 (56%) were classified as having MetS. In multivariable analysis, patients with MetS had greater odds of both grade ≥ 2 irAE (OR 2.82; 95% CI, 1.35-6.14; P = 0.007) and grade ≥ 3 irAE (OR 3.53; 95% CI 1.27-11.68; P = 0.02). However, MetS was not associated with pre-treatment cytokine levels. In contrast, ADI was associated with multiple inflammatory cytokines but not with MetS or irAE. CONCLUSIONS: MetS is associated with increased likelihood of moderate and severe irAE. The mechanism and mitigation of this risk merit further investigation.
Decorin facilitates T cell-mediated antitumor immunity and augments the efficacy of anti-PD1 immunotherapy.
Zheng N, Xiang L, Xu G … +7 more , Liu Y, Xu C, Zhang L, Zuo Y, Ye Z, Liu Y, Yang Z
Cancer Immunol Immunother · 2026 Jan · PMID 41591489 · Full text
BACKGROUND: Decorin (DCN) predominantly produced by fibroblasts is a small leucine-rich proteoglycan with tumor-suppressive property. However, whether DCN has a role in shaping the tumor immune microenvironment remains e...
BACKGROUND: Decorin (DCN) predominantly produced by fibroblasts is a small leucine-rich proteoglycan with tumor-suppressive property. However, whether DCN has a role in shaping the tumor immune microenvironment remains elusive. METHODS: The TCGA and GEO databases were analyzed to identify fibroblast-specific secretory proteins that are downregulated in most types of human tumors, positively correlate with CD8⁺ T cell infiltration, and associate with improved response to immune checkpoint blockade (ICB) therapy. The function of DCN in vivo was assessed using cell lines with stable DCN overexpression in both immunocompetent and immunodeficient mice. The changes in the composition and function of immune cell subpopulations in tumors were analyzed by flow cytometry analysis (FCM) and immunofluorescence staining. The role of CD8⁺ T cells in the DCN-mediated tumor suppression was further elucidated by utilizing B2m-knockout tumor cells and CD8⁺ T cell depletion assays. The in vitro co-culture system of tumor cells and T cells was applied to dissect the effects of DCN on CD8 T lymphocyte activation and functions. Finally, the therapeutic efficacy of DCN in combination with anti-PD1 antibody was evaluated in mouse tumor model. RESULTS: DCN-mediated tumor suppression was present in immunocompetent mice, wherein either depletion of CD8⁺ T cells in mice or ablation of β2M in tumor cells abrogated the tumor-inhibitory effects mediated by DCN, indicating the importance of CD8⁺ T cells in the DCN-antitumor activities. DCN overexpression promoted CD8⁺ T cell infiltration into tumors and increased the production of TNF-α, IFN-γ, and perforin in infiltrating T cells, and DCN expression substantially enhanced the tumor-suppressive efficacy of anti-PD1 therapy. More importantly, integrative analyses of clinical data indicated that DCN expression is downregulated in multiple types of human tumors and positively associated with the presence of CD8⁺ T cells and their expression of cytotoxic genes. Furthermore, high DCN levels were correlated with favorable prognosis in certain types of cancer patients with ICB therapy. CONCLUSIONS: Our study reveals that DCN functions as a tumor-suppressive factor by enhancing T cell response, and proposes the potential of exogenous DCN as a supplement to cancer immunotherapy.
Immunological profile of the tumor immune microenvironment of upper tract urothelial carcinoma predicts recurrence patterns.
Takahashi K, Ikarashi D, Kitano S … +9 more , Tamura D, Abe M, Ito A, Shiomi E, Maekawa S, Kato R, Kanehira M, Yanagawa N, Obara W
Cancer Immunol Immunother · 2026 Jan · PMID 41591483 · Full text
BACKGROUND: The association between the tumor immune microenvironment (TiME) in upper tract urothelial carcinoma (UTUC) and its prognosis remains unclear. We investigated the relationship between TiME and UTUC recurrence...
BACKGROUND: The association between the tumor immune microenvironment (TiME) in upper tract urothelial carcinoma (UTUC) and its prognosis remains unclear. We investigated the relationship between TiME and UTUC recurrence patterns. METHODS: We evaluated 90 patients who underwent nephroureterectomy for UTUC and divided them into nonrecurrence, distant metastasis, and intravesical recurrence-only groups. We assessed the association of the TiME with clinicopathological factors using surgical tissues and the prognosis of the three groups via multiplex fluorescence immunohistochemistry. RESULTS: The median age was 71 years (44-89), and 58 (64%) were male. Intratumoral CD4 T cell density was significantly higher in the nonrecurrence group (p = 0.0004) than the other groups, whereas intra- and peritumoral regulatory T cell (Treg; CD3CD4FoxP3 cell) density was higher in the distant metastases group than the intravesical recurrence-only group (p = 0.0025). In the multivariate analysis, pathological T stage and CD4 T cells, and pathological T stage and Treg were independent predictors of recurrence-free survival (p = 0.045, p = 0.017) and metastatic-free survival (p = 0.027, p = 0.011), respectively. CONCLUSIONS: Our study demonstrated that CD4 T cells and Tregs in the TiME of patients with UTUC were independent predictors of high-risk recurrence together with high pathological stage. The analysis of TiME in surgical specimens may provide an objective indicator of the efficacy of adjuvant therapy in UTUC.
Non-Genetically Modified Adoptive Cell Therapies for Solid Tumors: Current Landscape and Future Challenges.
Luo Q, Jiang W, Xie Y … +8 more , Dai Z, Zhu J, Du Y, Tao X, Lei Z, Chu X, Wang B, Fu G
Cancer Immunol Immunother · 2026 Jan · PMID 41591481 · Full text
Non-genetically modified adoptive cell therapies (ACTs) represent a rapidly advancing frontier in solid tumor immunotherapy, offering a safe and adaptable alternative to genetically engineered approaches by capitalizing...
Non-genetically modified adoptive cell therapies (ACTs) represent a rapidly advancing frontier in solid tumor immunotherapy, offering a safe and adaptable alternative to genetically engineered approaches by capitalizing on the intrinsic plasticity of immune cells. Genetic engineering strategies, including CAR-T cells, encounter significant obstacles in solid tumors, including on-target off-tumor toxicity, an immunosuppressive tumor microenvironment, and drug resistance. Although non-genetically modified ACTs-including tumor-infiltrating lymphocytes (TILs), cytokine-induced killer (CIK) cells, natural killer (NK) cells, and γδ T cells-offer unique advantages, their clinical application remains underexplored. This review consolidates the mechanistic basis, clinical progress, and limitations of non-genetically modified ACTs, proposing a paradigm shift toward combinatorial strategies. We systematically assessed how TILs overcome tumor microenvironment (TME) inhibition through lymphodepletion and cytokine assistance, compared the histocompatibility complex-unrestricted cytotoxicity of CIK cells with their functional diversity, and emphasized the innate flexibility of NK/γδ T cells against antigen-loss variants. By integrating preclinical and clinical data, we identify critical challenges: in vitro expansion inefficiency, absence of standardized protocols, and dynamic TME interactions. Furthermore, we advocated patient stratification by biomarkers, the addition of optimized cytokines, and rational combinations with checkpoint inhibitors or metabolic modulators to enhance efficacy. This review outlines the current landscape and proposes actionable solutions to reconcile the disparity between experimental potential and clinical applicability in non-genetically modified ACT.
Oligoclonal B cell expansion and passenger fusion genes predict response to Nivolumab in recurrent ovarian cancer: phase II Kyoto trial.
Murakami R, Hamanishi J, Brown JB … +9 more , Hosoe Y, Kobayashi T, Konishi T, Miyamoto T, Mizuno R, Taki M, Yamanoi K, Yamaguchi K, Mandai M
Cancer Immunol Immunother · 2026 Jan · PMID 41591474 · Full text
BACKGROUND: We previously reported a phase II Kyoto trial for platinum-resistant ovarian cancer (n = 20) using nivolumab (anti-programmed cell death-1 [PD-1] antibody). We evaluated the associations between clinical outc...
BACKGROUND: We previously reported a phase II Kyoto trial for platinum-resistant ovarian cancer (n = 20) using nivolumab (anti-programmed cell death-1 [PD-1] antibody). We evaluated the associations between clinical outcomes and transcriptomics and T and B cell clonality from tumor and blood cells. METHODS: We analyzed gene expression microarray with pre- and post-treatment peripheral blood mononuclear cells, α- and β-chain of T cell receptor (TCR) repertoires, and immunoglobulin G (IgG) and M of B cell receptor (BCR) repertoires in 61 samples from 19 patients. Shannon-Weaver diversity scores of the TCR and BCR repertoires were compared between responders and non-responders. RNA sequencing analyzed gene expression and fusion genes in tumor samples (n = 17). RESULTS: BCR repertoire analyses of post-/pre-treatment ratios in four responders (two patients with complete response (CR), one with partial response, and one with stable disease near to CR) revealed significantly decreased BCR-IgG repertoires diversity versus non-responders (Shannon-Weaver index, median 0.84 vs. 1.04, p < 0.05); the diversity of BCR-IgG repertoires recovered over 100 days. More than two passenger fusion genes were detected in six of the seven responders, whereas eight of the ten non-responders lacked fusion genes. The antitumor response significantly correlated with the number of fusion genes (p = 0.0006). Pathway analyses consistently identified immune-related processes, including cytokine-cytokine receptor interactions, neutrophil degranulation, and immunoregulatory interactions in both responders and tumors with high fusion gene counts. CONCLUSION: Transient oligoclonal expansion of B cells and passenger fusion genes might serve as predictive biomarkers of response to PD-1 blockade in ovarian cancer.
IRAK4 Regulates NF-κB signaling to suppress CD8 + T cell activity and promote immune evasion in glioblastoma development.
Xue Z, Song Z, Mo L … +2 more , Shi L, Yang S
Cancer Immunol Immunother · 2026 Jan · PMID 41591468 · Full text
Glioblastoma remains a highly aggressive brain tumor characterized by immune evasion, limiting the efficacy of immunotherapies. This study investigates the role of interleukin-1 receptor-associated kinase 4 (IRAK4) in mo...
Glioblastoma remains a highly aggressive brain tumor characterized by immune evasion, limiting the efficacy of immunotherapies. This study investigates the role of interleukin-1 receptor-associated kinase 4 (IRAK4) in modulating CD8 T cell activity and immune escape in glioblastoma development. Employing high-throughput proteomics, we identified 1,205 differentially expressed proteins in glioblastoma samples, with IRAK4 significantly upregulated. Bioinformatic analyses revealed IRAK4's involvement in the nuclear factor-kappa B (NF-κB) signaling pathway, critical for immune regulation. In vitro experiments demonstrated that IRAK4 overexpression suppressed CD8 T cell cytotoxicity, reducing lactate dehydrogenase release and cytokine production (interferon-gamma and tumor necrosis factor-alpha), while IRAK4 knockout enhanced these functions. Co-culture assays with glioblastoma cell lines (GL261 and G422) showed that IRAK4 overexpression promoted tumor cell proliferation, migration, and invasion, while decreasing apoptosis. Conversely, IRAK4 knockout attenuated these effects. Inhibition of NF-κB signaling with Triptolide reversed IRAK4-mediated suppression of CD8 T cell activity and tumor progression. Further investigations revealed that it can promote the phosphorylation of IκBα, leading to its ubiquitination and subsequent degradation, thereby activating the NF-κB signaling pathway and ultimately suppressing CD8⁺ T-cell activity. IN vivo, an orthotopic mouse model confirmed that IRAK4 overexpression increased tumor growth and reduced CD8 T cell infiltration, effects mitigated by Triptolide. These findings highlight IRAK4 as a key regulator of NF-κB-mediated immune evasion in glioblastoma, suggesting its potential as a therapeutic target to enhance CD8 T cell-based immunotherapy. This study provides novel insights into glioblastoma's immune regulatory mechanisms and supports the development of targeted immunotherapies.
Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.
Zhang Z, Cui D, Wang H … +2 more , Wu L, Liu X
Cancer Immunol Immunother · 2026 Jan · PMID 41591467 · Full text
Chimeric antigen receptor (CAR) T cell therapy has shown transformative success in hematologic malignancies, yet its application in solid tumors remains limited by a combination of intrinsic and extrinsic barriers. Intri...
Chimeric antigen receptor (CAR) T cell therapy has shown transformative success in hematologic malignancies, yet its application in solid tumors remains limited by a combination of intrinsic and extrinsic barriers. Intrinsically, CAR-T cells face challenges such as CAR instability, T cell exhaustion, insufficient tumor infiltration, and poor persistence. Extrinsically, the tumor microenvironment (TME) acts as a formidable obstacle, with physical barriers, metabolic constraints, and immunosuppressive signals that dampen CAR-T cell function. Recent advancements in CAR transduction, genetic reprogramming, and combination therapies have revealed novel strategies to overcome these hurdles. This review explores cutting-edge innovations aimed at unleashing the full potential of CAR-T therapy in solid tumors, focusing on strategies that enhance CAR-T cell function and persistence while addressing the immunosuppressive TME. By examining both intrinsic and extrinsic factors, we provide a comprehensive framework for future research and clinical application to improve CAR-T therapy for solid tumor treatment.
Empowering exhausted T cells of Glioblastoma patients by Neurotransmitters and Neuropeptides: decreasing immune checkpoint inhibitors, and increasing CD3zeta, proliferation and Glioblastoma arrest.
Levite M, Ilouz N, Galun E … +1 more , Shoshan Y
Cancer Immunol Immunother · 2026 Jan · PMID 41591460 · Full text
BACKGROUND: Glioblastoma is the most common malignant brain tumor, with extremely poor prognosis, and patient's T cells are exhausted, dysfunctional, and unable to eliminate Glioblastoma. To our knowledge, there is no ef...
BACKGROUND: Glioblastoma is the most common malignant brain tumor, with extremely poor prognosis, and patient's T cells are exhausted, dysfunctional, and unable to eliminate Glioblastoma. To our knowledge, there is no effective and safe treatment for rejuvenating and improving multiple functions of exhausted T cells. We previously found that specific Neurotransmitters and Neuropeptides induce direct, potent and beneficial effects on human T cells. METHOD: We studied if Dopamine, Glutamate, GnRH-II, Neuropeptide Y or their combinations, can rejuvenate and improve peripheral T cells of four Glioblastoma patients. RESULTS: The Glioblastoma patients had abnormally low numbers of T cells, and mostly small T cells. Single Ex-vivo treatment (24 h) of Glioblastoma patient's T cells with either Dopamine, Glutamate, GnRH-II, or Neuropeptide Y, or their combinations (10 M, without any antigen/mitogen/cytokine/growth factor), induced multiple beneficial effects: 1. increased the number of live T cells; 2. decreased simultaneously all tested exhaustion-related immune checkpoint inhibitors: PD-1, Tim-3, LAG-3, TIGIT and CD160; 3. increased expression of TCR-associated CD3zeta; 4. increased proliferation of patient's T cells in response to human Glioblastoma cells; and 5. dramatically increased arrest of Glioblastoma cells by Glioblastoma patient's T cells. CONCLUSIONS: Dopamine, Glutamate, Neuropeptide Y or GnRH-II, and the most beneficial being Dopamine + Neuropeptide Y, and Glutamate + Neuropeptide Y, can rejuvenate and improve Glioblastoma patient's T cells. They simultaneously decrease multiple immune checkpoint imhibitory receptors, and increase CD3zeta, T cell proliferation, and T cell anti-cancer activity. A novel 'Personalized Adoptive Neuro-Immunotherapy' was invented for Ex vivo rejuvenation and empowerment of patient's exhausted peripheral T cells by physiological Neurotransmitters/Neuropeptides, and their repeated infusion to patients.
Local-regional therapy plus ICIs, chemotherapy, and lenvatinib versus ICIs plus chemotherapy in advanced intrahepatic cholangiocarcinoma: a multicenter study.
Wang M, Li S, Yu G … +16 more , Zhang A, Ding S, Zhang Y, Feng S, Zhou Z, Piao M, Pan W, Li C, Sun B, Li J, Zhang N, Chen X, Sun Y, Zhang W, Zhu Z, Zhao H
Cancer Immunol Immunother · 2026 Jan · PMID 41591448 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) plus chemotherapy serve as the primary treatment for advanced intrahepatic cholangiocarcinoma (ICC), but they present limited effectiveness. This multicenter study intended...
BACKGROUND: Immune checkpoint inhibitors (ICIs) plus chemotherapy serve as the primary treatment for advanced intrahepatic cholangiocarcinoma (ICC), but they present limited effectiveness. This multicenter study intended to evaluate the feasibility of LRT plus ICIs, chemotherapy, and lenvatinib in patients with advanced ICC. METHODS: Patients receiving LRT-ICIs-Chemotherapy-Lenvatinib (LRT-ICI-Chemo-Len group, N = 66) or ICIs-Chemotherapy (ICI-Chemo group, N = 81) between April 2020 and May 2025 were enrolled. The study's outcomes included progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs). RESULTS: The LRT-ICI-Chemo-Len group showed notable enhancement in median PFS (9.9 months vs. 7.6 months, P = 0.004), median OS (20.9 months vs. 13.7 months, P = 0.004), objective response rate (ORR: 59.1% vs. 27.2%), and disease control rate (DCR: 93.9% vs. 84.0%). Conversion resection was performed in 8/66 (12.1%) in the LRT-ICI-Chemo-Len group, statistically higher than the 2.5% in the ICI-Chemo group. There was no statistically significant difference in the incidence of grade 3-4 AE between the LRT-ICI-Chemo-Len group (65.2%) and the ICI-Chemo group (56.8%) (P = 0.389). The most common grade 3-4 AE in the LRT-ICI-Chemo-Len group was myelosuppression. In the ICI-Chemo group, the most frequent grade 3-4 AE was myelosuppression. All AEs were manageable, with no grade 5 AE observed. CONCLUSIONS: Compared with the ICI-Chemo regimen, the LRT-ICI-Chemo-Len regimen significantly improved the prognosis of patients with advanced ICC. There was no significant difference in the incidence of grade 3-4 AEs between the two treatment regimens, and all AEs were manageable. This indicates that the LRT-ICI-Chemo-Len combination regimen is a feasible approach for the first-line treatment of advanced ICC.
Efficacy and prognostic model development of immune checkpoint inhibitor rechallenge in recurrent or metastatic nasopharyngeal carcinoma: a real-world study.
Jiang Y, Wu J, Dong S … +5 more , Zhang Z, Bei W, Zheng L, Xiang Y, Liu G
Cancer Immunol Immunother · 2026 Jan · PMID 41591431 · Full text
BACKGROUND: Immune checkpoint inhibitor (ICI) rechallenge in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) is a promising therapeutic strategy. We aim to assess its treatment outcomes and build prognostic mod...
BACKGROUND: Immune checkpoint inhibitor (ICI) rechallenge in recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) is a promising therapeutic strategy. We aim to assess its treatment outcomes and build prognostic models for clinical practice. METHODS: R/M NPC patients who failed prior anti-PD-1 immunotherapy and received ICI rechallenge were enrolled. Clinical features were recorded, and univariate and multivariate analysis was conducted to evaluate prognostic factors. Prognostic models were developed and validated to predict progression-free survival (PFS) and overall survival (OS), respectively. RESULTS: A total of 243 patients were enrolled between January 2019 and December 2023. The objective response rate (ORR) and disease control rate (DCR) for the entire cohort were 24.3% and 75.7%, respectively. After a median follow-up of 10.5 months, the median PFS was 6.3 months, the median duration of response (DOR) was 9.8 months, and the median OS was 19.8 months. Multivariate Cox analysis identified that the latest efficacy of anti-PD-1 therapy (HR 0.587, 95%CI 0.357-0.963, p = 0.035), EBV DNA level (HR 1.743, 95%CI 1.252-2.426, p = 0.001), locoregional therapy (HR 0.467, 95%CI 0.268-0.812, p = 0.007), and rechallenge with anti-PD-1 inhibitor (HR 1.548, 95%CI 1.005-2.385, p = 0.047) were independent statistically prognostic factors for PFS. Additionally, age (HR 2.044, 95%CI 1.297-3.222, p = 0.002), bone metastatic (HR 1.642, 95%CI 1.055-2.555, p = 0.028), and EBV DNA level (HR 1.673, 95%CI 1.034-2.706, p = 0.036) were independent significantly associated with OS. Prognostic models were developed based on the risk factors. Stratification of patients by the prognostic scores from these models showed that the low-risk group patients had significantly improved PFS and OS compared to their high-risk counterparts. CONCLUSIONS: This study provided a comprehensive assessment of the efficacy and prognostic factors of ICI rechallenge in RM-NPC patients who failed prior anti-PD-1 immunotherapy, and developed a prognostic model which could identify candidates for ICI rechallenge. Further prospective trials are warranted to confirm and expand these findings.
Comparison of induction chemotherapy with/without PD-1 inhibitors followed by concurrent chemoradiotherapy in locally advanced head and neck squamous cell carcinoma.
Yu Y, Jiao Z, Wu T … +6 more , Ning K, Cai T, Yang Z, Chen W, Jiang M, Yang A
Cancer Immunol Immunother · 2026 Jan · PMID 41484607 · Full text
BACKGROUND: Locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains a disease with a challenging prognosis. Concurrent chemoradiotherapy has long been the standard of care, yet efforts to enhance outcom...
BACKGROUND: Locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains a disease with a challenging prognosis. Concurrent chemoradiotherapy has long been the standard of care, yet efforts to enhance outcomes through the addition of induction or adjuvant therapies have largely failed. Recently, immune checkpoint inhibitors, particularly PD-1 inhibitors, have demonstrated efficacy in managing HNSCC, becoming a first-line treatment for recurrent/metastatic cases. This study aims to evaluate whether adding PD-1 inhibitors to induction chemotherapy can improve long-term outcomes in newly diagnosed LA HNSCC patients. PATIENTS AND METHODS: This retrospective analysis included 204 newly diagnosed LA HNSCC patients treated between February 2012 and February 2023. Patients were divided into two cohorts: TPI group (n=115), who received induction chemotherapy including PD-1 inhibitors, and TP group (n=89), who received induction chemotherapy alone. The primary outcome was overall survival (OS), while secondary outcomes included progression-free survival (PFS) and objective response rate (ORR). Baseline characteristics were balanced using overlap propensity score weighting. Survival analyses were conducted using the Kaplan-Meier method, and subgroup analyses employed Cox proportional hazards models. RESULTS: With a median follow-up of 29.23 months, baseline characteristics were balanced after weighting. The addition of PD-1 inhibitors significantly improved OS (HR: 0.11, 95% CI: 0.03-0.37, p<0.001) and PFS (HR: 0.43, 95% CI: 0.20-0.89, p=0.024). Furthermore, the TPI group showed a significant improvement in the best radiological responses (p=0.02). Subgroup analyses identified specific factors associated with enhanced PFS and OS. CONCLUSIONS: The addition of PD-1 inhibitors to induction chemotherapy significantly improves overall survival in patients with LA HNSCC, underscoring the potential for further clinical trials to refine and optimize treatment strategies.
Combinatorial approaches for cancer immunotherapy.
Spada S, Oweida A
Cancer Immunol Immunother · 2026 Jan · PMID 41484592 · Full text
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