Roles of KDM5 demethylases in therapeutic resistance of cancers

Deciphering the changes in the tumor and tumor microenvironment (TME) that accompany metastatic disease progression is essential if we are to identify potential new anti-cancer treatments. In particular, a complete understanding of how cancer subclones and TME evolve over time from primary disease to death, both independently and in relation to one another, and of the impact of therapies such as immunotherapy (IO) on TME composition and architecture, remain lacking. In this work, we sought to profile the changes in both cancer-cell intrinsic genomic immune evasion and TME that accompany lung cancer progression from diagnosis to death. To do this, we applied multiple orthogonal methods (whole-exome sequencing; RNAseq; imaging mass cytometry) to >500 longitudinally collected primary, pre-mortem metastatic, and postmortem metastatic tumor samples from 23 patients with non-small cell lung cancer (NSCLC) co-recruited to the UK national TRACERx (TRAcking Cancer Evolution through therapy [Rx], NCT01888601) and PEACE (Posthumous Evaluation of Advanced Cancer Environment) autopsy studies. Samples covered multiple organ sites and were derived from both patients who did and did not receive IO, allowing analysis of the differential impact of treatment on end-stage disease profiles. Sequencing analyses suggest that heterogeneous mechanisms of immune evasion develop at distinct metastatic sites, and between metastases and the primary tumor. Profiling of TME indicated a global reduction in immune cell densities in metastatic compared to primary tumor samples and a skewing towards cytotoxic and terminally differentiated CD8 T cell subtypes. Previous work had identified four major TME architectures in primary NSCLC, based on the abundance and location of tumor infiltrating lymphocytes, macrophages and neutrophils, including a neutrophil-rich TME found to be associated with metastasis. In this work, we identified new TME classes found in metastatic samples, including those dominated by myeloid cells in the stroma. Two new TME classes, predominantly comprised of post-mortem metastatic samples from IO-treated patients, were significantly enriched in tumor-infiltrating cytotoxic CD8 T cells compared to other classes. TMEs of regions within the same metastasis were found to be more similar to each other than to those of primary tumor regions. Using computational approaches to track cancer subclones, we reconstructed metastatic migration histories for each patient and found that the TMEs of source and target metastases in a met-met migration pair were more similar than those from pairs of metastases from the same patient without a direct migration path. Our findings provide insights into the relationships between genetic immune evasion and immune cell infiltration across the lung cancer disease course. Citation Format: Sonya Hessey, Mihaela Angelova, Emma Colliver, Katey S. Enfield, Kerstin Haase, Michelle M. Leung, Corentin Richard, Robert Bentham, Clare Puttick, Oriol Pich, Wing Kin Liu, Alastair Magness, Abigail Bunkum, Kristiana Grigoriadis, Ariana Huebner, David A. Moore, Monica Sivakumar, Roberto Salgado, Philip S. Hobson, Dina Levi, Sophia Ward, Selvaraju Veeriah, Cristina Naceur-Lombardelli, Andrew Rowan, Crispin T. Hiley, Simone Zaccaria, Nicholas McGranahan, Charles Swanton, Mariam Jamal-Hanjani. The evolution of immunity and immune evasion from early- to end-stage lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1207.

Dysregulated expression of the suppressors of cytokine signaling (SOCS) contributes to the development of prostate cancer

Simple SummaryAs the long-term effects of radiotherapy on the quality of life (QoL) of elderly (≥65 years) patients with head-and-neck squamous cell carcinoma (HNSCC) are not well understood, we examined the QoL of surviving elderly HNSCC patients who were treated with radiotherapy. In this cross-sectional study, long-term quality of life (QoL) at ≥1 year after radiotherapy completion was comparable to the general German population of the same age and gender. Patients whose HNSCC was induced by human papillomavirus (HPV) exhibited a superior long-term global QoL than elderly patients with HPV-negative tumors. Interestingly, concomitant chemotherapy administration did not deteriorate patients’ global QoL in the long-term. We did not observe differences in patients’ health-related QoL in dependence of the treatment (definitive versus adjuvant (chemo)radiotherapy). Our data are important for clinicians treating elderly HNSCC patients as well as for elderly HNSCC patients themselves.The effects of radiotherapy on the long-term quality of life (QoL) of surviving elderly HNSCC patients are not well understood, therefore, we analyzed QoL in this population. A cross-sectional analysis was performed at a tertiary cancer center to assess long-term QoL in elderly HNSCC patients. Eligible patients were ≥65 years at the time of treatment who had to be alive for ≥1 year after radiotherapy and without current anti-cancer treatment. QoL and patient satisfaction were assessed using the EORTC QLQ-C30, QLQ-H&N35 and ZUF-8 questionnaires, respectively, and treatment-related toxicities were graded according to CTCAE (Common Terminology Criteria of Adverse Effects) v.5.0. Seventy-four patients met the inclusion criteria, of which 50 consented to participate. Median time between radiotherapy and QoL assessment was 32 months (range 12–113). The QLQ-C30 global QoL median amounted to 66.7 points (interquartile range (IQR) 50.0–83.3), which was comparable to the age- and gender-adjusted German population (median 65.3). Median global QoL was similar between patients undergoing definitive (75.0, IQR 50.0–83.3) and adjuvant (chemo)radiotherapy (66.7, IQR 41.7–83.3, p = 0.219). HPV-positive HNSCC patients had superior global QoL after radiotherapy than their HPV-negative counterparts (p < 0.05), and concomitant chemotherapy did not influence the long-term QoL (p = 0.966). Median global QoL did not correspond with physician-assessed highest-graded chronic toxicities (p = 0.640). The ZUF-8 ranged at 29 points in median (IQR 27–31), showing high patient satisfaction. Surviving elderly HNSCC patients treated by radiotherapy exhibit a relatively high long-term global QoL which is a relevant information for clinicians treating elderly HNSCC patients.

Long-Term Quality of Life (QOL) After Chemo-IMRT for Locally Advanced Oropharyngeal Cancer (OPC): A Prospective Longitudinal Study

Gliomas are the most common primary malignant tumors of the central nervous system (CNS), and despite progress in molecular diagnostics and targeted therapies, their prognosis remains poor. In recent years, immunotherapy has emerged as a promising treatment modality in cancer therapy. However, the inevitable immune evasion by tumor cells is a key barrier affecting therapeutic efficacy. Epigenetic regulation, such as DNA methylation, histone modification, and non-coding RNA expression, plays a crucial role in the occurrence, development, and immune evasion of gliomas. These modifications can dynamically regulate gene expression, leading to the silencing of tumor-associated antigens, dysregulation of pro-inflammatory cytokines, and dynamic modulation of immune checkpoints (such as PD-L1). This review systematically elucidates the key mechanisms by which epigenetic regulation promotes immune evasion in gliomas and details three interconnected mechanisms: 1) epigenetic silencing of tumor-associated antigens and antigen-presenting machinery; 2) dysregulation of pro-inflammatory cytokine secretion; and 3) dynamic modulation of PD-L1 expression through chromatin remodeling. We emphasize the potential of combining epigenetic therapies with immunotherapies to enhance anti-tumor immune responses and overcome treatment resistance in gliomas. Future research should focus on developing biomarker-driven epigenetic immunotherapies and exploring the complex interplay between epigenetic modifications, glioma cells, and the tumor immune microenvironment to improve patient outcomes.

Simple SummaryProstate cancer is the most common malignancy in men, with a high mortality rate when disease progresses to metastasis and therapeutic resistance. Evidence implicates inflammation as a driver of prostate cancer risk and has a significant impact on processes in the tumor microenvironment that facilitate progression to advanced therapeutically resistant disease. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Full understanding of the role of inflammation in prostate cancer progression to advanced metastatic disease and tumor relapse will aid in the development of personalized predictive biomarkers and therapy to reduce the burden and mortality in prostate cancer patients.Prostate cancer is the most common malignancy among men, and progression to metastasis and the emergence of therapeutically resistant disease confers a high mortality rate. Growing evidence implicates inflammation as a driver of prostate cancer development and progression, resulting in increased cancer risk for prostate cancer. Population-based studies revealed that the use of antinflammatory drugs led to a 23% risk reduction prostate cancer occurrence, a negative association that was stronger in men who specifically used COX-2 inhibitors. Furthermore, patients that were taking aspirin had a 21% reduction in prostate cancer risk, and further, long-term users of daily low dose aspirin had a 29% prostate cancer risk reduction as compared to the controls. Environmental exposure to bacterial and viral infections, exposure to mutagenic agents, and genetic variations predispose the prostate gland to inflammation, with a coordinated elevated expression of inflammatory cytokines (IL-6, TGF-β). It is the dynamics within the tumor microenvironment that empower these cytokines to promote survival and growth of the primary tumor and facilitate disease progression by navigating the immunoregulatory network, phenotypic epithelial-mesenchymal transition (EMT), angiogenesis, anoikis resistance, and metastasis. In this review, we discuss the sources of inflammation in the prostate, the functional contribution of the critical inflammatory effectors to prostate cancer initiation and metastatic progression, and the therapeutic challenges that they impose on treatment of advanced disease and overcoming therapeutic resistance. Growing mechanistic evidence supports the significance of inflammation in localized prostate cancer, and the systemic impact of the process within the tumor microenvironment on disease progression to advanced therapeutically-resistant prostate cancer. Rigorous exploitation of the role of inflammation in prostate cancer progression to metastasis and therapeutic resistance will empower the development of precise biomarker signatures and effective targeted therapeutics to reduce the clinical burden and lethal disease in the future.

Gastric cancer (GC) remains a leading cause of cancer-related mortality globally, with persistent challenges in overcoming treatment resistance and recurrence. Lactic acid was once considered a metabolic waste, but now it is considered a multifunctional coordinator of GC progression. This review synthesizes emerging evidence on lactate’s multifaceted roles in GC progression, elucidating lactate&amp;apos;s multifaceted roles in GC pathogenesis, including its regulation of tumor metabolic heterogeneity, epigenetic reprogramming, and immune microenvironment remodeling. Lactate fosters metabolic symbiosis between glycolytic and oxidative tumor cells, sustains chemoresistance via histone lactylation, RNA methylation, and chromatin phase separation, and promotes the immunosuppressive tumor microenvironment (TME) remodeling and immune evasion by suppressing CD8+ T-cell function and polarizing tumor-associated macrophages (TAMs) towards an M2 phenotype. and polarizing tumor-associated macrophages. Critically, lactate synergizes with Helicobacter pylori (Hp) to form a microbiome-metabolite axis that amplifies bacterial virulence, induces genomic instability, and accelerates malignant transformation. Therapeutic strategies targeting lactate production (LDH-A inhibitors), transport (MCT1/4 blockers), and signaling (epigenetic modulators/lactylation inhibitors) show promise in disrupting these oncogenic circuits. Nanotechnology-driven approaches and microbiome modulation (engineered probiotics) further enhance precision delivery and efficacy. Understanding the interplay between lactate, the tumor microenvironment (TME), and microbial communities offers novel avenues for overcoming therapeutic resistance and improving GC outcomes.

The tumor microenvironment (TME) is critical for cancer initiation, growth, metastasis, and therapeutic resistance. The extracellular matrix (ECM) is a significant tumor component that serves various functions, including mechanical support, TME regulation, and signal molecule generation. The quantity and cross-linking status of ECM components are crucial factors in tumor development, as they determine tissue stiffness and the interaction between stiff TME and cancer cells, resulting in aberrant mechanotransduction, proliferation, migration, invasion, angiogenesis, immune evasion, and treatment resistance. Therefore, broad knowledge of ECM dysregulation in the TME might aid in developing innovative cancer therapies. This review summarized the available information on major ECM components, their functions, factors that increase and decrease matrix stiffness, and related signaling pathways that interplay between cancer cells and the ECM in TME. Moreover, mechanotransduction alters during tumorogenesis, and current drug therapy based on ECM as targets, as well as future efforts in ECM and cancer, are also discussed.

Long-Term Patient-Reported Quality of Life of Anal Cancer Survivors Treated With Intensity Modulated Radiation Therapy and Concurrent Chemotherapy: Results From a Prospective Phase II Trial

BackgroundMolecular targeted therapies have shown considerable efficacy in treating metastatic renal cell carcinoma (mRCC). However, many patients still experience tumor recurrence or metastasis due to drug resistance. Despite extensive research on resistance mechanisms, there is a lack of comprehensive bibliometric studies examining the overall characteristics of targeted therapy resistance in renal cell carcinoma.Materials and methodsPublications on resistance to targeted therapy in renal cell carcinoma were identified from the Web of Science Core Collection (WoSCC) from June 2004 to November 2024. The English-language literature was analyzed using bibliometric tools, including VOSviewer and CiteSpace, to examine publication trends, active countries/regions, key authors, and institutions. Keyword analysis, co-citation mapping, and gene identification were conducted to uncover research trends and focal points.ResultsA total of 1081 publications were identified, with the United States, China, and Italy as the top contributing countries. Prominent institutions included the Cleveland Clinic, the Sloan Kettering Cancer Center, the MD Anderson Cancer Center, Fudan University, and Huazhong University of Science and Technology. Camillo Porta was a prolific author, and Brian I. Rini was among the most highly cited. The journal Cancers published the most papers in this field, and the Journal of Clinical Oncology was the most co-cited. Key research topics included the “tumor microenvironment” and “combination therapy”. A comprehensive analysis of publications related to "the tumor microenvironment" reveals that "renal cancer stem cells" and "epithelial-mesenchymal transition" have been identified as key terms strongly associated with therapeutic resistance mechanisms in targeted cancer treatments. In-depth analysis of the regulatory molecules and molecular mechanisms in the literature highlighted the roles of microRNA and the synergistic effects between anti-PD-L1/PD-1 and targeted drugs.ConclusionsBibliometric analysis of research on molecular targeted therapy resistance in renal cell carcinoma revealed a clear trajectory and rapidly increasing trend in this field. The impact of the tumor microenvironment, particularly the roles of renal cancer stem cells and epithelial-mesenchymal transition, has garnered significant attention. Additionally, the combination of anti-PD-L1/PD-1 and targeted drugs, as well as the involvement of miRNA, have emerged as key areas of focus. As understanding of this field deepens, future research is expected to uncover novel therapeutic targets and more effectively overcome the challenges of targeted therapy resistance in renal cell carcinoma, ultimately improving patient outcomes.

Objective: To analyze the effects of multidisciplinary specialized nursing care on the short and long-term postoperative quality of life in patients with pancreatic cancer. Methods: This is a randomized controlled trial. In this study, 88 patients with pancreatic cancer who were treated at our hospital between January 2021 and January 2022 were recruited and allocated 1:1 either to receive into routine nursing care (n=44, routine group) or interdisciplinary specialist nursing care (n=44, study group). The outcome measures in both groups included surgery-related indices, short and long-term quality of life, and adverse responses. Results: There were no participants who dropped out of this study due to treatment intolerance, nor were there any additional participants. Patients in the study group had significantly shorter recovery time from gastrointestinal function, bed rest and hospital stay than those in the conventional group (P&lt;0.05). Before the intervention, there was no significant difference in the quality of life between the two groups (P&gt;0.05); 3 months and 1 year after the intervention, the quality of life of patients in the study group was higher than that of patients in the conventional group (P&lt;0.05). The overall incidence of adverse reactions was significantly lower in the study group than in the conventional group (P&lt;0.05). Conclusion: Multidisciplinary specialized nursing care produces an ideal clinical outcome for postoperative patients with pancreatic cancer. It substantially reduces recovery time, boosts short and long-term postoperative quality of life, and diminishes the incidence of adverse reactions in patients. This protocol merits clinical application.

Clinical equipoise remains significant for the treatment of Grade IV pancreatic injuries in stable patients (i.e., drainage vs. resection). The literature is poor in regards to experience, confirmed main pancreatic ductal injury, nuanced multidisciplinary treatment, and long-term patient quality of life (QOL). The primary aim was to evaluate the management and outcomes (including long-term QOL) associated with Grade IV pancreatic injuries. All severely injured adult patients with pancreatic trauma (1995-2020) were evaluated (Grade IV injuries compared). Concordance of perioperative imaging, intraoperative exploration, and pathological reporting with a main pancreatic ductal injury was required. Patients with resection of Grade IV injuries were compared with drainage alone. Long-term QOL was evaluated (Standard Short Form-36). Of 475 pancreatic injuries, 36(8%) were confirmed as Grade IV. Twenty-four (67%) underwent a pancreatic resection (29% pancreatoduodenectomy; 71% extended distal pancreatectomy [EDP]). Patient, injury and procedure demographics were similar between resection and drainage groups (p > 0.05). Pancreas-specific complications in the drainage group included 92% pancreatic leaks, 8% pseudocyst, and 8% walled-off pancreatic necrosis. Among patients with controlled pancreatic fistulas beyond 90 days, 67% required subsequent pancreatic operations (fistulo-jejunostomy or EDP). Among patients whose fistulas closed, 75% suffered from recurrent pancreatitis (67% eventually undergoing a Frey or EDP). All patients in the resection group had fistula closure by 64 days after injury. The median number of pancreas-related health care encounters following discharge was higher in the drainage group (9 vs. 5; p = 0.012). Long-term (median follow-up = 9 years) total QOL, mental and physical health scores were higher in the initial resection group (p = 0.031, 0.022 and 0.017 respectively). The immediate, intermediate and long-term experiences for patients who sustain Grade IV pancreatic injuries indicate that resection is the preferred option, when possible. The majority of drainage patients will require additional, delayed pancreas-targeted surgical interventions and report poorer long-term QOL. Epidemiology/Prognostic, Level III.

Decoding TAGLN2 in cancer: the molecular linchpin bridging actin remodeling, immune dysregulation and therapeutic challenges.

Tumor subclones refer to distinct cell populations within the same tumor that possess different genetic characteristics. They play a crucial role in understanding tumor heterogeneity, evolution, and therapeutic resistance. The formation of tumor subclones is driven by several key mechanisms, including the inherent genetic instability of tumor cells, which facilitates the accumulation of novel mutations; selective pressures from the tumor microenvironment and therapeutic interventions, which promote the expansion of certain subclones; and epigenetic modifications, such as DNA methylation and histone modifications, which alter gene expression patterns. Major methodologies for studying tumor subclones include single-cell sequencing, liquid biopsy, and spatial transcriptomics, which provide insights into clonal architecture and dynamic evolution. Beyond their direct involvement in tumor growth and invasion, subclones significantly contribute to tumor heterogeneity, immune evasion, and treatment resistance. Thus, an in-depth investigation of tumor subclones not only aids in guiding personalized precision therapy, overcoming drug resistance, and identifying novel therapeutic targets, but also enhances our ability to predict recurrence and metastasis risks while elucidating the mechanisms underlying tumor heterogeneity. The integration of artificial intelligence, big data analytics, and multi-omics technologies is expected to further advance research in tumor subclones, paving the way for novel strategies in cancer diagnosis and treatment. This review aims to provide a comprehensive overview of tumor subclone formation mechanisms, evolutionary models, analytical methods, and clinical implications, offering insights into precision oncology and future translational research.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and its onset and progression are closely associated with epigenetic modifications, particularly post-translational modifications of histones (HPTMs). In recent years, advances in mass spectrometry (MS) have revealed a series of novel HPTMs, including succinylation (Ksuc), citrullination (Kcit), butyrylation (Kbhb), lactylation (Kla), crotonylation (Kcr), and 2-hydroxyisobutyrylation (Khib). These modifications not only expand the histone code but also play significant roles in key carcinogenic processes such as tumor proliferation, metastasis, and metabolic reprogramming in HCC. This review provides the first comprehensive analysis of the impact of novel HPTMs on gene expression, cellular metabolism, immune evasion, and the tumor microenvironment. It specifically focuses on their roles in promoting tumor stem cell characteristics, epithelial–mesenchymal transition (EMT), and therapeutic resistance. Additionally, the review highlights the dynamic regulation of these modifications by specific enzymes, including “writers,” “readers,” and “erasers.”