Clinical & Translational Oncology[JOURNAL]
Sun
200 papers
Patient stratification in exercise oncology: matching exercise modalities to immune phenotypes to optimize immunotherapy response.
Zeng L, Du X, Yang Z … +5 more , Wu Y, Tang M, Liang F, Chen L, Ye X
Transl Oncol · 2026 Jul · PMID 42398463 · Publisher ↗
Despite advances in oncology, the clinical response to treatments, particularly immunotherapy, remains highly variable due to the complex tumor immune microenvironment. While regular exercise is recognized as a supportiv...
Despite advances in oncology, the clinical response to treatments, particularly immunotherapy, remains highly variable due to the complex tumor immune microenvironment. While regular exercise is recognized as a supportive intervention to improve patient outcomes, its mechanistic integration into personalized cancer care is limited by a generalized approach to physical activity. In this review, we argue that the heterogeneity of exercise benefits stems from modality-specific immune remodeling. Evidence indicates that distinct exercise types elicit specific "immune stimulation fingerprints". Steady-state aerobic exercise primarily resolves chronic inflammation and promotes immune homeostasis; resistance training preserves the muscle-immune axis, providing critical physical and immune reserves to maintain treatment tolerance; and high-intensity interval training can provoke acute mobilization of effector immune cells. Importantly, the ability of these systemic immune adaptations to enhance treatment response depends heavily on the local tumor immune niche. To bridge the gap between systemic exercise effects and clinical outcomes, we propose the "exercise-immune matching window" model. This framework highlights that improving therapeutic efficacy-and potentially optimizing responses to immunotherapy-requires patient stratification. By aligning specific exercise modalities with the individual's baseline immunophenotype (e.g., chronic inflammation, significant immunosuppression, or immunosenescence) and treatment stage, we can maximize synergistic effects. Ultimately, transitioning from generic exercise recommendations to tailored, immune-directed prescriptions offers a practical strategy to augment comprehensive cancer management.
REG4 serves as a prognostic biomarker for pancreatic cancer with long-standing diabetes mellitus by modulating chemoresistance.
Choi JI, Park HJ, Park H … +10 more , Cho Y, Shin HS, Koh YI, Lee SY, Jang SI, Cho JH, Kim HS, Hwang HK, Rim JH, Lim JB
Transl Oncol · 2026 Jul · PMID 42398462 · Publisher ↗
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) in patients with diabetes mellitus (DM) represents a clinically heterogeneous subgroup, yet biomarkers that reflect diabetes-associated tumor biology and chemotherapy r...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) in patients with diabetes mellitus (DM) represents a clinically heterogeneous subgroup, yet biomarkers that reflect diabetes-associated tumor biology and chemotherapy response remain limited. In particular, the influence of diabetes duration on treatment resistance in PDAC is poorly understood. METHODS: We performed an integrated translational analysis combining reanalysis of public single-cell RNA sequencing (scRNA-seq) datasets, clinical serum biomarker profiling, and functional validation using pancreatic cancer cell lines and patient-derived organoids. Circulating REG4 concentrations were measured in independent PDAC cohorts and correlated with diabetes duration, overall survival, and response to FOLFIRINOX. Functional relevance was assessed under diabetes-mimicking hyperglycemic conditions. RESULTS: Single-cell transcriptomic analysis demonstrated enrichment of REG4-expressing tumor cells within the classical PDAC subtype specifically in diabetic patients. Clinically, circulating REG4 concentrations were significantly elevated in PDAC patients with long-standing diabetes, and high REG4 levels were associated with poor overall survival and resistance to FOLFIRINOX exclusively in this subgroup. In contrast, no prognostic association was observed in non-diabetic or new-onset diabetic patients. In patient-derived organoids and pancreatic cancer cell lines, chronic glucose exposure induced REG4 expression, activation of WNT/β-catenin signaling, suppression of apoptotic pathways, and increased resistance to FOLFIRINOX, recapitulating key clinical features of long-standing diabetes-associated PDAC. CONCLUSIONS: These findings suggest REG4 as a candidate diabetes duration-dependent prognostic and predictive biomarker in pancreatic cancer, warranting validation in larger prospective cohorts. By linking metabolic context to chemotherapy resistance through REG4-associated signaling, this study provides a translational framework for patient stratification and treatment optimization in diabetes-associated PDAC.
Integrated multi-omics and single-cell analysis of galectins and immune associations in triple-negative breast cancer.
Ji P, Liu H, Di GH … +2 more , Shao ZM, Gong Y
Transl Oncol · 2026 Jul · PMID 42391674 · Publisher ↗
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Galectins, a family of β-galactoside-binding lectins, have emerged as important mediators of tumor-immune in...
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Galectins, a family of β-galactoside-binding lectins, have emerged as important mediators of tumor-immune interactions, but their cell-type-specific expression patterns and functional roles within the tumor microenvironment of TNBC remain poorly defined. METHODS: We integrated bulk transcriptomic and genomic data from FUSCC (n = 465) and TCGA (n = 161) TNBC cohorts with single-cell RNA sequencing data from 26 treatment-naïve patients. We systematically assessed galectin expression, genomic alterations, prognostic significance, associations with immune checkpoints and immune infiltration, and cell-type-specific patterns linked to immune contexts and therapeutic response. RESULTS: Galectin family members showed broad dysregulation in TNBC, with recurrent copy number alterations contributing to transcriptional heterogeneity. At the bulk level, LGALS2 was associated with favorable survival, while LGALS3 predicted poor prognosis. Several galectins, including LGALS2, LGALS9, and LGALS10, exhibited positive correlations with immune checkpoint expression and enriched immune infiltration, particularly involving CD8⁺ T cells and tumor-infiltrating lymphocytes. Single-cell analysis revealed distinct galectin expression across malignant, immune, and stromal compartments, suggesting heterogeneous transcriptomically inferred immune contexts. Galectin expression also differed by treatment response: pathological complete response (pCR) to neoadjuvant chemo-immunotherapy was associated with higher LGALS3 and lower LGALS2, LGALS8, and LGALS9, while pCR to chemotherapy was linked to higher LGALS9 and lower LGALS1. CONCLUSIONS: Our study comprehensively characterizes galectin family members in TNBC, revealing their prognostic significance and association with tumor microenvironment and treatment response, and highlighting the clinical and translational relevance of galectins as candidate biomarkers and hypothesis-generating molecules for future mechanistic studies.
Single-cell and machine learning-based neural regulation signature for prognosis prediction and immunotherapy response in lung adenocarcinoma.
Zheng Y, Miao X, Wang Y … +2 more , Wei S, Zhang Q
Transl Oncol · 2026 Jul · PMID 42391672 · Publisher ↗
OBJECTIVE: Lung adenocarcinoma (LUAD) molecular heterogeneity limits traditional prognostic models. Given the emerging role of neural regulation (NR) in tumor progression, we aimed to delineate NR-associated cellular phe...
OBJECTIVE: Lung adenocarcinoma (LUAD) molecular heterogeneity limits traditional prognostic models. Given the emerging role of neural regulation (NR) in tumor progression, we aimed to delineate NR-associated cellular phenotypes via single-cell RNA sequencing (scRNA-seq) and develop a robust machine-learning-derived signature (NR.Sig) to precisely assess prognosis and guide personalized immunotherapy. METHODS: We integrated three LUAD scRNA-seq cohorts and ten transcriptomic cohorts with immunotherapy records. Single-cell analyses (clustering, cell-cell communication, pseudotime trajectory) identified NR-enriched epithelial subpopulations. Using their prognostic marker genes, we evaluated 101 combinations from 10 machine learning algorithms via leave-one-out cross-validation. The combination yielding the highest C-index formed the NR.Sig model. Its prognostic accuracy, stability, and clinical utility in characterizing the tumor immune microenvironment (TME) and forecasting immunotherapy efficacy were comprehensively validated across multiple independent cohorts. RESULTS: "CRABP2-positive epithelial cells" were identified as a stem-like, NR-enriched malignant subpopulation correlating strongly with immune exhaustion. The random survival forest (RSF)-based NR.Sig achieved optimal modeling performance. Validation confirmed that NR.Sig high-risk patients had significantly shorter overall and progression-free survival. NR.Sig outperformed conventional clinical indicators and existing prognostic models, with FAM83A identified as the core hub gene. Crucially, high-risk scores inversely correlated with immune infiltration. Conversely, the low-risk group exhibited an "immune-hot" phenotype with enhanced cancer-immunity cycle activity and elevated checkpoint expression, translating to significantly higher immunotherapy response rates in independent clinical cohorts. CONCLUSION: By integrating scRNA-seq with an optimized machine learning framework, we developed and validated NR.Sig. This robust signature holds significant clinical translational value, serving as a precise molecular tool for LUAD risk stratification, prognostic assessment, and the guidance of personalized immunotherapy strategies.
Baseline value and longitudinal kinetics of circulating nucleosomes during neo-adjuvant chemotherapy in newly diagnosed ovarian cancer: Results from a GINECO/GINEGEPS study of the randomized phase II CHIVA trial.
Corbaux P, Colomban O, Lescuyer G … +27 more , Ray-Coquard I, De Rauglaudre G, Joly F, Abdeddaim C, Combe P, Blonz C, Bataillon G, Meunier J, Alexandre J, Berton D, Kaminsky MC, Bello Roufai D, Leary A, Venat L, Dohollou N, Louvet C, Lebreton C, Abadie-Lacourtoisie S, Lotz JP, Favier L, Fabbro M, Bonichon-Lamichhane N, Kurtz JE, Follana P, Pujade-Lauraine E, Payen L, You B
Transl Oncol · 2026 Jul · PMID 42385345 · Publisher ↗
PURPOSE: Circulating nucleosomes (DNA wound around histone proteins) are emerging cancer biomarkers. We investigated their association with clinical outcomes in advanced ovarian cancer. PATIENTS AND METHODS: Circulating...
PURPOSE: Circulating nucleosomes (DNA wound around histone proteins) are emerging cancer biomarkers. We investigated their association with clinical outcomes in advanced ovarian cancer. PATIENTS AND METHODS: Circulating levels and longitudinal kinetics of two nucleosomes (H3K27Me3 and H3K36Me3, log-scale) were assessed at baseline, during neoadjuvant chemotherapy after interval cytoreductive surgery, and at progression in patients with advanced ovarian cancer patients from the randomized phase II CHIVA trial. Nucleosomes were measured with Nu.Q® immunoassays,compared to those from 201 healthy subjects, and analyzed in relation to surgical outcomes, progression-free survival, with respect to the modeled CA-25 ELIMination rate constant K (KELIM) along with established clinical covariates. RESULTS: H3K27Me3 and H3K36me3 nucleosome concentrations were available for 148/188 patients. Both nucleosomes were significantly higher in ovarian cancer patients compared with healthy controls and showed correlated baseline levels. Lower baseline H3K36Me3 was independently associated with complete interval cytoreduction surgery and progression-free survival, complementary to CA-25 KELIM. Longitudinal changes in nucleosome levels showed a decrease during neoadjuvant chemotherapy, but were not associated with radiological response, completeness of interval cytoreductive surgery or progression-free survival. CONCLUSION: Baseline H3K36Me3 and H3K27Me3 levels may represent non-invasive biomarkers in advanced ovarian cancer and warrant further evaluation for their potential clinical utility.
Fractionated high-dose vitamin c sustains higher plasma trough concentrations in advanced solid tumors: a phase I clinical study.
Yin Q, Wang Y, Wu H … +7 more , Wang Q, Xu H, Long X, Peng J, Wu J, Zhou F, Yang L
Transl Oncol · 2026 Jun · PMID 42378816 · Publisher ↗
High-dose vitamin C (HDVC) has a short half‑life of approximately 2 h, and once‑daily dosing results in sub‑therapeutic plasma concentrations for most of the dosing interval, potentially limiting its pro‑oxidant antitumo...
High-dose vitamin C (HDVC) has a short half‑life of approximately 2 h, and once‑daily dosing results in sub‑therapeutic plasma concentrations for most of the dosing interval, potentially limiting its pro‑oxidant antitumor activity. In this phase I study, 18 patients with advanced solid tumors were assigned to three cohorts (n = 6 each): Group A (0.5 g/kg once daily, total daily dose 0.5 g/kg), Group B (0.5 g/kg every 12 h, total daily dose 1.0 g/kg), and Group C (0.75 g/kg every 12 h, total daily dose 1.5 g/kg). Plasma trough concentrations were measured daily for 7 days. Compared to Group A, Group B exhibited significantly higher trough concentrations throughout the study (P < 0.05), demonstrating superior maintenance of therapeutic levels. Further dose escalation to 0.75 g/kg twice daily (Group C) provided no additional trough concentration benefit versus Group B (P > 0.05), consistent with the plateau in peak concentrations at single doses above approximately 70 g/m² (∼1.0 g/kg). All regimens were well tolerated, with only one mild nausea (5.6%) and no serious adverse events. Fractionated dosing (0.5 g/kg every 12 h) significantly improves trough concentration maintenance with good tolerability. This optimized regimen (total daily dose 1.0 g/kg) provides a rational pharmacokinetic basis for future phase II trials designed to evaluate whether sustained pro‑oxidant levels translate into enhanced clinical efficacy.
Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.
Qiu S, Li S, Chen Y … +3 more , Ma X, Fu H, Zhao B
Transl Oncol · 2026 Jun · PMID 42378815 · Publisher ↗
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although substantial advances in chemotherapy, molecular targeted therapy, and immunotherapy have improved clinical out...
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although substantial advances in chemotherapy, molecular targeted therapy, and immunotherapy have improved clinical outcomes in select patient populations, therapeutic resistance remains the major obstacle to durable disease control. Accumulating evidence suggests that drug resistance in CRC does not result from isolated molecular events, but rather reflects a dynamic and adaptive process driven by coordinated tumor intrinsic programs, as well as continuous interactions between tumor cells and their surrounding microenvironment. In this Review, we present a systematic overview of the clinical manifestations and biological foundations of resistance to cytotoxic chemotherapy, targeted therapy, and immune checkpoint blockade in CRC. We summarize tumor intrinsic resistance mechanisms, including oncogenic signaling reprogramming, DNA damage response modulation, metabolic and redox adaptation, ubiquitin-regulated proteostasis, epigenetic and RNA-mediated regulation, evasion of programmed cell death, and the emergence of cancer stem cell and drug-tolerant persister states. In parallel, we examine the contribution of the tumor microenvironment, including cancer-associated fibroblasts, immunosuppressive immune networks, extracellular vesicle-mediated communication, and the gut microbiota, in establishing protective niches that promote resistance and limit therapeutic efficacy. We further discuss how emerging approaches such as single-cell and spatial multi-omics profiling, liquid biopsy, and longitudinal molecular monitoring have reshaped the understanding of drug resistance as a continuous evolutionary process under therapeutic selection pressure. Finally, we highlight therapeutic strategies inspired by systems biology and evolutionary principles, with an emphasis on rational combination and sequencing regimens, targeting adaptive vulnerabilities, and remodeling the tumor ecosystem to enable more durable and precise control of CRC.
Establishment of a clear cell renal cell carcinoma organoid cohort integrated into the UroCCR clinical database: A feasibility study.
Lefranc R, Waeckel T, Riffet M … +9 more , Florent R, Desmartin G, Lecouflet L, Divoux J, Poulain L, Tillou X, Weiswald LB, Levallet G, Bazille C
Transl Oncol · 2026 Jun · PMID 42372405 · Publisher ↗
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the sixth most common cancer in France. While early-stage survival rates are high in early stages, they decrease significantly in metastatic stages, due to tumor het...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the sixth most common cancer in France. While early-stage survival rates are high in early stages, they decrease significantly in metastatic stages, due to tumor heterogeneity and treatment resistance. The development of reliable preclinical models is essential to improve targeted therapies. This study aimed to evaluate the feasibility of establishing patient-derived ccRCC organoids linked to the UroCCR clinical database. METHODOLOGY: Tumor samples from total or partial nephrectomies performed at Caen University Hospital between November 2023 and March 2024 were processed for organoid culture. Seven culture conditions were tested, including different extracellular matrices (Matrigel, collagen I) and growth factor-enriched media. RESULTS: Organoids were established in 12 of 18 cases (66.7%). Among these, five cultures were successfully expanded and characterized histologically (42%). Organoids were maintained in culture for a median of 52 days and underwent a mean of two passages. Histological analyses showed that organoids retained several morphological features consistent with the original tumors, although variability in CA-IX and CK7 expression was observed. SIGNIFICANCE: This feasibility study demonstrates that ccRCC organoid generation from surgical specimens is achievable but remains limited by variable establishment rates and culture duration. Further optimization and integration of microenvironmental components will be necessary to enhance the translational relevance of this model.
Pan-cancer analysis identifies immunoproteasome as the predominant survival-associated component of antigen processing machinery.
Lai JI, Liu CY, Tsai YF … +3 more , Huang CC, Tseng LM, Chao TC
Transl Oncol · 2026 Jun · PMID 42364494 · Full text
Neoantigens are critical targets for cancer immunotherapy, yet the relationship between experimentally validated neoantigen burden and antigen processing machinery (APM) expression in determining clinical outcomes remain...
Neoantigens are critical targets for cancer immunotherapy, yet the relationship between experimentally validated neoantigen burden and antigen processing machinery (APM) expression in determining clinical outcomes remains unclear. We mapped CEDAR-annotated neoantigens (CENs) onto mutation data from 43,980 patients across 14 cancer types using cBioPortal. APM gene expression was correlated with survival outcomes across 13 cohorts. Machine learning approaches (elastic net stability selection, random survival forest, univariable Cox regression) identified prognostically important APM genes across 11 cohorts. Findings were validated in the IMvigor210 immunotherapy trial (n=348 metastatic urothelial carcinoma patients) and single-cell RNA-sequencing data (GSE161529; n=29 breast cancers). Overall, 40.4% of patients harbored at least one CEN, with high prevalence in pancreatic (>75%) and skin cancers (>70%). CENs predominantly arose from driver oncogenes including PIK3CA, KRAS, BRAF, TP53, and EGFR. High APM expression was associated with improved survival, particularly in CEN-positive tumors. Machine learning identified immunoproteasome components (PSME1, PSMB8, PSMB9, PSMB10) as the dominant prognostic contributors within the 12-gene APM signature. A simplified 4-gene immunoproteasome score performed equivalently to the full APM score in leave-one-cohort-out cross-validation (median C-index 0.545 vs 0.545; p=0.31). In IMvigor210, immunoproteasome-high patients achieved a 3.2-fold higher response rate to atezolizumab (19.8% vs 6.2%; p=0.010). Single-cell analysis confirmed that tumor-intrinsic immunoproteasome expression correlated with increased CD8+ T cell infiltration (p=0.0014) and total immune fraction (p=0.0002). The 4-gene immunoproteasome signature demonstrates robust prognostic and predictive value across bulk sequencing, clinical trial, and single-cell platforms, warranting prospective validation as an immunotherapy biomarker.
S100A10 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating JUND/TNC axis-mediated EMT.
Zheng Z, Peng A, Xi Z … +6 more , Ou H, Liu J, Ye A, Shao J, Li F, Liu Y
Transl Oncol · 2026 Jun · PMID 42361687 · Full text
BACKGROUND: Recurrence and metastasis significantly impact the prognosis of lung adenocarcinoma (LUAD), yet effective therapies targeting these processes remain limited, especially in advanced stages. This study investig...
BACKGROUND: Recurrence and metastasis significantly impact the prognosis of lung adenocarcinoma (LUAD), yet effective therapies targeting these processes remain limited, especially in advanced stages. This study investigates the role of S100A10 as an oncogenic driver in LUAD progression via epithelial-mesenchymal transition (EMT). METHODS: S100A10 expression was analyzed in public datasets and correlated with patient survival. Functional studies involved S100A10 knockdown or overexpression in LUAD cell lines, assessing viability (CCK-8), migration, invasion (Transwell, wound healing), mRNA (qPCR), and protein (Western blot). Tumorigenicity was evaluated using in vivo models. A small-molecule inhibitor, [D-Leu-4]-OB3, was identified through virtual screening and tested for its effect on S100A10 and LUAD. RESULTS: High S100A10 expression correlated with poor outcomes in LUAD. Knockdown of S100A10 suppressed cell viability, migration, invasion, and EMT both in vitro and in vivo, while overexpression enhanced these malignant traits. Mechanistically, S100A10 activated JUND and Tenascin-C (TNC), promoting EMT. Re-expression of TNC rescued the anti-metastatic effects of S100A10 inhibition. [D-Leu-4]-OB3 specifically targeted S100A10, inhibiting LUAD growth and metastasis. CONCLUSION: S100A10 promotes LUAD progression and metastasis through JUND/TNC-mediated EMT. [D-Leu-4]-OB3 represents a promising targeted therapy for LUAD by inhibiting S100A10.
Establishment, biobanking, and multi-omics characterization of 41 patient-derived colorectal cancer organoids: MYC/PRC classification.
Lee YJ, Park JH, Nam HJ … +5 more , Kim SC, Kim MJ, Jeong SY, Park JW, Ku JL
Transl Oncol · 2026 Jun · PMID 42349318 · Full text
PURPOSE: Colorectal cancer (CRC) exhibits marked genetic, transcriptomic, and phenotypic heterogeneity, limiting the robustness of existing molecular classification systems. We aimed to apply and validate an SMI-based MY...
PURPOSE: Colorectal cancer (CRC) exhibits marked genetic, transcriptomic, and phenotypic heterogeneity, limiting the robustness of existing molecular classification systems. We aimed to apply and validate an SMI-based MYC/PRC classification framework in CRC patient-derived organoids and to characterize its molecular, pharmacologic, and clinical relevance across independent cohorts. METHODS: We established 41 CRC PDOs from 28 patients and performed whole-exome sequencing, RNA sequencing, and high-throughput drug screening. SMI scores (-1 to 1) were used to classify PDOs as MYC-type (stem-like) or PRC-type (differentiated). A concordantly classified subset of 25 PDOs underwent integrative multi-omics analyses. Findings were validated in an expanded cohort of 181 CRC PDOs and in TCGA-COAD. We compared pathway activities, mutational profiles, and drug responses, and performed archetypal modeling (K = 2) to position samples along a MYC-PRC transcriptional continuum. RESULTS: MYC-type PDOs exhibited enrichment of cell-cycle and proliferation-related programs, whereas PRC-type PDOs showed differentiation-associated transcriptional programs, including coagulation and NF-κB signaling. Drug screening showed greater sensitivity of MYC-type PDOs to MEK/EGFR-targeted agents, whereas PRC-type PDOs displayed more heterogeneous responses. Archetypal modeling preserved the α(PRC)-α(MYC) trade-off and sample ordering across feature sets and larger cohorts. Validation in the expanded PDO dataset and TCGA-COAD reproduced subtype-specific transcriptional patterns and supported their clinical relevance. CONCLUSIONS: SMI-based MYC/PRC classification captures biologically coherent tumor states with distinct molecular features and therapeutic sensitivities. This transcriptome-based framework complements existing classification systems and may support subtype-informed therapeutic prioritization in CRC.
PD-1/PD-L1 immune checkpoint inhibitors in Hodgkin lymphoma: A meta- and network meta-analysis.
Zhu T, Liu Z, Sun H … +3 more , Lin T, Lu Z, Yang X
Transl Oncol · 2026 Jun · PMID 42349316 · Full text
BACKGROUND: Hodgkin lymphoma (HL) is a relatively rare lymphoid malignancy that significantly affects the health of adolescents, young adults and the elderly. Even though conventional chemotherapy offers high cure rates,...
BACKGROUND: Hodgkin lymphoma (HL) is a relatively rare lymphoid malignancy that significantly affects the health of adolescents, young adults and the elderly. Even though conventional chemotherapy offers high cure rates, the relapsed/refractory HL remains challenging. METHODS: Pooled single-arm and network meta-analyses were used. Literature search was conducted in PubMed, Embase, Web of Science, the Cochrane Library and Clinical Trials, et al., from the date of establishment dates to August 31, 2025. Studies were screened based on inclusion and exclusion criteria. The primary outcome analyzed was complete response rate (CRR), partial response rate (PRR), and objective response rate (ORR). RESULTS: 11 single-arm trials and five controlled trials, involving 1602 participants and seven ICI-based treatment strategies were included. The meta-analysis revealed an overall CRR of 0.35, a PRR of 0.37, and an ORR of 0.75 across all therapy methods. Of these, one ICI drug in combination with conventional therapy demonstrated the highest CRR and ORR, while camrelizumab achieved the highest PRR. The treatment strategies with the highest CRR in network meta-analysis was the combination of two ICI drugs. The strategies with the highest PRR were camrelizumab, a single ICI drug, while the strategies with the highest ORR was a single ICI drug combined with conventional therapy. CONCLUSION: This study suggests that camrelizumab is associated with an improved PRR for HL, whereas, combination strategy of two ICI drugs, and that one of pembrolizumab and camrelizumab combined with conventional chemoradiotherapy are more effective for elevating the CRR and ORR respectively.
Comprehensive analysis of antibody-drug conjugate (ADC) targets in adenoid cystic carcinoma: examining antigen expression in relation to clinicopathological features, prognosis, and initial therapeutic outcomes.
Wang Y, Dou S, Jiang W … +5 more , Zhu L, Liu S, Gu T, Zhu G, Li J
Transl Oncol · 2026 Jun · PMID 42341371 · Full text
Effective systemic therapy for refractory or recurrent/metastatic adenoid cystic carcinoma (ACC) remains an unmet clinical need. Although antibody-drug conjugates (ADCs) have revolutionized treatment for other solid tumo...
Effective systemic therapy for refractory or recurrent/metastatic adenoid cystic carcinoma (ACC) remains an unmet clinical need. Although antibody-drug conjugates (ADCs) have revolutionized treatment for other solid tumors, their application in ACC is limited by an inadequate understanding of targetable antigen expression. We performed immunohistochemical analysis of five ADC targets (EGFR, TROP2, B7-H4, Nectin-4, and AXL) across 265 ACC cases (193 non-solid subtype and 72 solid subtype) and examined their expression in relation to clinicopathological features, histological subtypes, and prognosis. Additionally, we conducted preliminary biomarker-guided ADC therapy in two selected patients. EGFR and TROP2 were frequently expressed at moderate-to-high levels (81% of cases for EGFR and 77% for TROP2), mainly in non-solid ACC, with high expression rates of 72% and 55%, respectively. Conversely, B7-H4 and Nectin-4 showed moderate-to-high expression in 59% and 55% of the overall cohort, but were notably enriched in the aggressive solid subtype, with high expression observed in 66% and 75% of cases, respectively. AXL expression was either negative or low. High B7-H4 and Nectin-4 expression levels were independently associated with reduced overall survival (p < 0.05), whereas EGFR and TROP2 expression showed no significant prognostic value. Importantly, early clinical studies demonstrated that the EGFR-targeted ADC MRG003 and the TROP2-targeted ADC Sac-TMT showed notable efficacy in patients with refractory ACC and high expression of these targets. This pioneering study introduces a biomarker-based stratification system, categorizing ACC patients by histological subtype and target expression profiles, EGFR/TROP2 for non-solid ACC and B7-H4/Nectin-4 for solid ACC, to inform ADC therapy decisions.
Clinical translation of an immunomodulatory cell therapy that is designed to convert "cold" tumors to "hot": A phase 2B trial in 3L MSS/pMMR metastatic colorectal cancer.
Hirschfeld A, Al Hallak MN, Cusnir M … +5 more , Yang X, Piyapan P, Lausoontornsiri W, Shane R, Har-Noy M
Transl Oncol · 2026 Jun · PMID 42335577 · Full text
BACKGROUND: A translational immunotherapy framework was designed to initiate sequential spatial and temporal immunomodulatory cascades using living, allogeneic, activated memory Th1 cells (AlloStim®), hypothesized to pro...
BACKGROUND: A translational immunotherapy framework was designed to initiate sequential spatial and temporal immunomodulatory cascades using living, allogeneic, activated memory Th1 cells (AlloStim®), hypothesized to promote an immunomodulatory cascade in immunologically "cold" tumors. Microsatellite stable/proficient mismatch repair (MSS/pMMR) metastatic colorectal cancer (CRC) represents an immunotherapy-refractory "cold" tumor archetype with historically low response rates. METHODS: To evaluate this framework, a Phase 2B, single-arm, multi-center proof-of-concept trial was conducted in third-line MSS/pMMR metastatic CRC patients, utilizing overall survival (OS) as the primary endpoint. AlloStim® was administered via a sequential schedule of weekly intradermal priming and subsequent intravenous infusions over three 5-week cycles, followed by optional monthly intravenous boosters. RESULTS: Twenty-nine patients were enrolled (18 death events, 11 censored cases [37.9%]). The median OS was 16.4 months (492 days; 95% CI: 8.6-20.8 months). To account for non-proportional hazards, Restricted Mean Survival Time (RMST) evaluated at a 32-month temporal horizon demonstrated an average cohort life expectancy of 16.1 months (482 days; 95% CI: 12.3-19.8 months). Concurrently, 89% of evaluable patients met RECIST 1.1 criteria for progressive disease at Day 119, highlighting a profound survival-radiological discordance. The protocol was well tolerated; only 4% of total adverse events were ≥ Grade 3. CONCLUSION: This study provides indirect clinical observations supporting the hypothesis that an active immunomodulatory framework may elicit an encouraging survival signal and extended life expectancy in refractory metastatic MSS/pMMR CRC, despite conventional radiological progression. These findings justify evaluation in a prospective, randomized controlled trial powered to validate this translational strategy.
Perioperative ctDNA as a prognostic biomarker in endometrial cancer - the CODEC study.
Delahunty RL, Jayawardana M, Arnolda R … +27 more , Koh TT, Hofman MS, Reid K, Lamont J, Nguyen-Ngo C, Johnston HM, Brooks NG, Wojtowicz P, Obers VJ, Jobling T, Shadbolt C, Smith PE, Sawyer BL, Xu H, Silva SSM, Neesham D, Ellis J, Goss G, Volchek M, Jones K, Hewitt CA, Fellowes A, Prince HM, McNally O, Wong SQ, Christie EL, Yannakou CK
Transl Oncol · 2026 Jun · PMID 42330843 · Full text
PURPOSE: Biomarkers to predict relapse and guide adjuvant therapy selection are needed in endometrial cancer (EC), one of the few cancers increasing in incidence and mortality. Assessment of circulating tumour DNA (ctDNA...
PURPOSE: Biomarkers to predict relapse and guide adjuvant therapy selection are needed in endometrial cancer (EC), one of the few cancers increasing in incidence and mortality. Assessment of circulating tumour DNA (ctDNA) at multiple perioperative time points has not been explored in EC. This study aimed to evaluate the prognostic utility of ctDNA across four perioperative time points, explore ctDNA dynamics, and compare ctDNA-derived tumour burden with 18F-fluorodeoxyglucose (FDG)-PET/CT and MRI. PATIENTS AND METHODS: Participants with Type 2 EC planned for surgery and consenting to the collection of biospecimens were enrolled prior to surgery and followed prospectively. Participants had preoperative imaging, and tumour sequencing was performed using hybrid capture, which guided the design of droplet digital PCR (ddPCR) assays for ctDNA analysis. The primary study endpoint was relapse free survival. RESULTS: Fifty participants were enrolled in the CODEC study. Genomic findings were consistent with the established molecular landscape of EC. Detection of ctDNA postoperatively at 24 h (Time Point 2B) and at 2-6 weeks (Time Point 3) was associated with poorer relapse-free survival. No significant association with outcome was observed for preoperative (Time Point 1) or intraoperative (Time Point 2A) ctDNA. Preoperative ctDNA correlated with FDG-PET- and MRI-defined tumour volume. CONCLUSION: These findings are hypothesis-generating and support the prognostic relevance of postoperative ctDNA assessment in EC with the 2-6 week postoperative window the most clinically informative time point for detecting minimal residual disease. Further studies are required to validate these findings and determine whether ctDNA can guide adjuvant therapy selection.
PRDX4 expression potentially links redox adaptation to oncogenic signaling and tumor progression in pancreatic ductal adenocarcinoma.
Liu Y, Han J, Shioya A … +5 more , Oyama T, Guo X, Yang Q, Uramoto H, Yamada S
Transl Oncol · 2026 Jun · PMID 42322696 · Full text
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive behavior, therapeutic resistance, and redox imbalance. Peroxiredoxin 4 (PRDX4), an endoplasmic reticulum-localized antioxidant enzyme, ha...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive behavior, therapeutic resistance, and redox imbalance. Peroxiredoxin 4 (PRDX4), an endoplasmic reticulum-localized antioxidant enzyme, has been implicated in tumor progression, but its clinical significance and redox-associated role in PDAC remain unclear. METHODS: PRDX4 expression was assessed by immunohistochemistry in 128 resected PDAC specimens and correlated with clinicopathological features and disease-specific survival (DSS). Functional effects were examined in PRDX4-overexpressing PDAC cell lines. Intracellular reactive oxygen species (ROS) were evaluated under basal and oxidative stress conditions, with N-acetyl-l-cysteine (NAC) rescue. Signaling and redox-related proteins were analyzed by Western blotting. A PRDX4-transgenic mouse model was used to evaluate tumor growth, angiogenesis, and gemcitabine (GEM) responsiveness. RESULTS: High PRDX4 expression was associated with aggressive clinicopathological features and poor DSS. PRDX4 overexpression promoted cell proliferation and migration and reduced intracellular ROS levels. NAC treatment diminished ROS differences, supporting ROS-dependent redox modulation. PRDX4 overexpression was associated with increased ERK phosphorylation, suppressed JNK phosphorylation, increased total PI3K/AKT and p38 levels, reduced E-cadherin expression, and upregulation of NRF2 and HO-1. PRDX4 expression positively correlated with NRF2 and HO-1 in clinical specimens. In vivo, PRDX4 overexpression promoted tumor growth, increased microvessel density, and reduced GEM sensitivity. CONCLUSIONS: PRDX4 is associated with aggressive tumor behavior, redox adaptation, and might reduce gemcitabine responsiveness in PDAC in vivo, supporting its potential as a prognostic biomarker and a candidate molecule for future therapeutic investigation.
Targeted inhibition of ATR kinase promotes antitumor immunity in HNSCC through enhanced STING activation and T cell function.
da Costa FH, Kawabe M, Tsai TY … +10 more , Okamoto K, Bartels MD, Cortes S, Veeramachaneni R, Rangel R, Frederick MJ, Sandulache VC, Sikora AG, Myers JN, Osman AA
Transl Oncol · 2026 Jun · PMID 42322694 · Publisher ↗
OBJECTIVES: Oral cavity head and neck squamous cell carcinoma (HNSCC) represents a major global health burden, with over 40,000 new cases annually in the United States and >500,000 worldwide. Despite advances in surgery,...
OBJECTIVES: Oral cavity head and neck squamous cell carcinoma (HNSCC) represents a major global health burden, with over 40,000 new cases annually in the United States and >500,000 worldwide. Despite advances in surgery, radiation therapy, chemotherapy, and immunotherapy, overall survival rates have remained largely stagnant over the past three decades, and over half of patients ultimately die from the disease. Although immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients with recurrent or metastatic HNSCC, the majority gain limited benefit. Thus, novel therapeutic strategies that enhance responses to immunotherapy are urgently needed. The ATR-CHK1 signaling pathway has recently been implicated in immune modulation, suggesting that ATR inhibition may potentiate antitumor immunity. This study investigates the therapeutic efficacy of the novel ATR inhibitor AZD6738, alone and in combination with anti-PD-1 therapy, in a syngeneic mouse model of HNSCC. MATERIALS AND METHODS: An orthotopic syngeneic mouse model was used to assess in vivo treatment efficacy. Immune profiling of tumors following AZD6738 treatment was performed by immunohistochemistry and flow cytometry. Conditioned medium from cocultures of tumor and bone marrow cells treated with AZD6738 was analyzed by flow cytometry to evaluate immune cell populations. Additional coculture experiments with bone marrow-derived cells and splenic T cells assessed T cell activation and proliferation. In vitro assays, including clonogenic survival, western blotting, and ATR shRNA knockdown, were used to confirm drug specificity and explore molecular mechanisms. RNA sequencing of tumor samples was conducted to evaluate cytokine expression and immune-related gene signatures. RESULTS: AZD6738 significantly enhanced the efficacy of anti-PD-1 therapy by remodeling the tumor microenvironment. Treatment increased cytotoxic T cell infiltration and activity while reducing regulatory T cells and immunosuppressive myeloid cells. ATR inhibition promoted M1 macrophage polarization and modulated cytokines supporting T cell activation. Mechanistically, enhanced immune responses were associated with DNA damage-induced activation of the cGAS/STING pathway and reduced STAT3 phosphorylation. Transcriptomic analyses revealed that combination therapy upregulated interferon signaling and suppressed epithelial-mesenchymal transition pathways in the MOC1 tumor model. CONCLUSION: AZD6738 enhances antitumor immunity through cytotoxic T cells and innate immune mechanisms, supporting its further development in combination with anti-PD-1 therapy for HNSCC.
A spatial immune scoring system based on the tumor microenvironment features improves prognostic stratification in lung adenocarcinoma.
Luo W, Jia J, Wang Q … +13 more , Li X, Yang F, Zhao Y, Li Z, Li L, Wang X, Meng M, Guo H, Zheng W, Wang L, Li D, Hou Z, Guo Y
Transl Oncol · 2026 Jun · PMID 42320171 · Full text
The spatial heterogeneity of the tumor immune microenvironment (TME) in lung adenocarcinoma (LUAD) limits the prognostic accuracy of traditional TNM staging. Moreover, conventional T cell based immune scores established...
The spatial heterogeneity of the tumor immune microenvironment (TME) in lung adenocarcinoma (LUAD) limits the prognostic accuracy of traditional TNM staging. Moreover, conventional T cell based immune scores established for other solid tumors fail to effectively stratify patient outcomes in LUAD. To address this, we applied quantitative multiplex immunofluorescence to map the spatial immune contexture of LUAD and developed the Lung Cancer Immune Score (LCIS). This framework integrates four key biomarkers: CD68⁺HLA-DR⁺ macrophages, CD20⁺ B cells, PD-1⁺ cells and Ki67⁺ proliferating tumor cells, to quantify the balance between tumor proliferation and host anti-tumor immunity across the tumor core and invasive margin. High LCIS scores independently predicted improved overall survival in both the discovery (p = 0.02) and independent validation (p = 0.017) cohorts, outperforming conventional clinical parameters and single biomarkers. Specifically, LCIS effectively sub-stratified patients with Stage II and III LUAD into refined prognostic groups, resolving the prognostic ambiguity within the same TNM stage. Overall, by quantifying the interaction between tumor proliferation and antigen-directed immune activation, the LCIS serves as a spatial biomarker to refine prognosis and inform personalized therapy in LUAD.
Single-cell and spatial transcriptomics reveal lactate-active epithelial-immune cell crosstalk that reprograms the immune microenvironment in colorectal cancer.
Lan H, Li Y, Li H … +3 more , Guo J, Wang C, Tang Q
Transl Oncol · 2026 Jun · PMID 42320170 · Full text
The metabolic reprogramming of tumor microenvironment is a critical driver of colorectal cancer (CRC) pathogenesis. In this context, dysregulated lactate metabolism plays a pivotal role in immunosuppression and therapeut...
The metabolic reprogramming of tumor microenvironment is a critical driver of colorectal cancer (CRC) pathogenesis. In this context, dysregulated lactate metabolism plays a pivotal role in immunosuppression and therapeutic resistance. Integrating single-cell transcriptomics, spatial transcriptomics, and bulk sequencing datasets, this research delineated the lactate metabolic landscape across colorectal cancer (CRC) tumor ecosystems. Single-cell profiling revealed significant metabolic activity in both the epithelial and myeloid compartments. Consequently, a lactate metabolism score (LMscore) was developed, which is based on four core genes (COX15, SLC25A13, COX10, MPC1). An elevated LMscore has been demonstrated to reprogram epithelial developmental trajectories and reconfigure intercellular communication networks, notably through EFNA1-EPHA3-mediated crosstalk with fibroblasts and endothelial cells. Spatial transcriptomics corroborated intimate spatial colocalization and metabolic pathway co-enrichment between lactate-active epithelia and fibroblasts. Clinically, high LMscore independently predicts a decreased overall survival across multiple cohorts and defines a "cold" tumor immune phenotype. This phenotype is characterized by an accumulation of immunosuppressive cells including M2 macrophages and cancer-associated fibroblasts (CAFs) and a reduction in effector T-cell infiltration. This ultimately results in a refractory response to immune checkpoint blockade. Mechanistically, COX15 emerges as a central regulator of lactate metabolic dysregulation, coinciding with fibroblast-derived TGF-β secretion and immunosuppressive niche formation. Functional validation confirms that COX15 targeting suppresses tumor proliferation. This work establishes LMscore as a clinically robust biomarker for prognostication and immunotherapy response prediction, thereby providing a mechanistic foundation for metabolic reprogramming-targeted combinatorial therapies in CRC.
PYCR1 induces ferroptosis via the PI3K/Akt signaling pathway to regulate the proliferation and migration of osteosarcoma.
Hu J, Huang Y, Chen H … +4 more , Xie Z, Yan H, Li H, Li R
Transl Oncol · 2026 Jun · PMID 42320169 · Full text
Osteosarcoma treatment outcomes are compromised by increased drug resistance, distant metastasis, and tumor recurrence. While Pyrrolidine-5-carboxylic acid reductase 1(PYCR1) knockdown has been shown to inhibit tumor pro...
Osteosarcoma treatment outcomes are compromised by increased drug resistance, distant metastasis, and tumor recurrence. While Pyrrolidine-5-carboxylic acid reductase 1(PYCR1) knockdown has been shown to inhibit tumor proliferation and migration in certain cancers. Its effects in osteosarcoma and regulatory mechanisms within osteosarcoma cells have not been explored. This study investigated the role of PYCR1 in osteosarcoma proliferation and its potential molecular mechanisms. The expression of PYCR1 was assessed in osteosarcoma tissues by immunohistochemistry and its correlation with clinical outcomes was determined. Subsequently, lentivirus-mediated knockdown and over expression of PYCR1 was achieved in osteosarcoma cells to evaluate its impact on proliferation, colony formation, and migration ability. The PI3K/Akt signaling pathway and its downstream effector COL1A1 were investigated using a combination of biomarker analysis, transcriptome sequencing, and co-immunoprecipitation assays. Subsequent silencing of COL1A1 induced phenotypic changes and confirmed tumorigenicity in vivo. The ferroptosis agonist Erastin and its specific antagonist Ferrostatin-1 (Fer-1) were combined with PYCR1 knockdown to explore their correlation with ferroptosis. By applying the pathway inhibitor LY294002, it was confirmed that the PI3K/Akt pathway is crucial for osteosarcoma proliferation. This study confirms that PYCR1 drives osteosarcoma cell proliferation and migration through three key mechanisms: regulating downstream genes, inhibiting ferroptosis, and activating the PI3K/Akt signaling pathway.
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