In a remarkable series of scientific advancements, researchers at the City of Hope cancer research and treatment center have unveiled critical insights spanning RNA modifications in cancer, innovative immunotherapy timing in lung cancer, stem cell therapy for neurological disorders, and groundbreaking discoveries in immune regulation. These cutting-edge studies not only deepen our understanding of complex disease mechanisms but also open promising new avenues for therapeutic intervention.

A key focus of the research has been on the multifaceted roles of RNA chemical modifications in driving cancer behavior. More than 170 distinct RNA modifications have now been cataloged, including prominent types like N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine. These modifications regulate cellular processes by determining RNA localization, stability, and translational efficiency, thereby influencing protein synthesis. Systems biology investigators Dr. Xiaolan Deng and Dr. Jianjun Chen have provided a comprehensive framework linking specific RNA regulators to oncogenic pathways. Their work emphasizes the transformative potential of targeting RNA modifications as precise biomarkers and therapeutic targets, heralding a new era of RNA-centric precision oncology.

Concurrently, a pivotal clinical investigation led by radiation oncologist Dr. Kristin Higgins has reshaped the strategy for administering immunotherapy in limited-stage small cell lung cancer (SCLC). Despite high hopes, concurrent use of immune checkpoint inhibitors alongside chemoradiation failed to yield survival benefits or improved tumor control. Instead, delayed immunotherapy—administered subsequent to radiation—emerged as the more efficacious approach, suggesting that the immunomodulatory dynamics of timing govern therapeutic outcomes. These findings refine clinical protocols for integrating powerful immuno-oncology agents in aggressive lung malignancies.

In the realm of neurological disorders, City of Hope scientists achieved a striking preclinical milestone by demonstrating that human stem cell–derived brain cells can halt and reverse pre-existing brain damage in a mouse model of Canavan disease. This fatal infantile leukodystrophy results from a deficiency of the enzyme aspartoacylase, compromising myelin synthesis and neural function. The transplanted engineered stem cells not only replenished the missing enzyme but promoted remyelination, enhanced brain tissue health, and improved motor function months post-treatment. Crucially, the intervention remained effective despite administration after symptom onset, a vital consideration given the diagnostic challenges in such neurodegenerative conditions.

The innovative application of artificial intelligence (AI) has further augmented disease management, with a novel machine learning model identifying socioeconomic and neighborhood determinants as primary predictors for missed lung cancer screening follow-ups. Led by surgeon-scientist Dr. Loretta Erhunmwunsee and AI specialist Dr. Kun-Han Lu, this approach moves beyond traditional risk factors like smoking history to encompass social determinants of health, enabling early identification of patients at risk for screening non-compliance. This paradigm shift holds the potential to tailor community outreach and navigation efforts, ultimately improving early lung cancer detection.

Immunological research at City of Hope has unveiled a previously unrecognized subset of CD8+ T cells expressing CD318, exhibiting regulatory properties pivotal for tempering immune responses. Contrary to long-held dogma restricting immune regulation to certain cell types, this study led by immunologist Dr. Helena Reijonen reveals these CD318-positive cytotoxic T cells function like immune brakes, preventing excessive or aberrant immune activation. Understanding their role could lead to novel therapies for autoimmune diseases such as type 1 diabetes by enhancing immune tolerance mechanisms.

Further expanding the landscape of immune regulation, investigators discovered the protein TDRD3 as an essential orchestrator in the differentiation of induced regulatory T cells (iTregs). iTregs serve as critical suppressors of immune inflammation, and the absence of TDRD3 culminated in systemic inflammatory phenotypes in aging mouse models. This work, led by Dr. Yanzhong “Frankie” Yang and immunology professor Dr. Zuoming Sun, elucidates the epigenetic and molecular controls governing immune homeostasis. Targeting TDRD3 pathways offers translational promise for managing autoimmune and inflammatory disorders by reestablishing immune equilibrium.

Citizens of the oncology and biomedical fields have also recognized scientific leadership and excellence at City of Hope. Dr. John D. Carpten received the prestigious Allen Lichter Visionary Leader Award from the American Society of Clinical Oncology (ASCO), honoring his pivotal contributions in advancing cancer care. Likewise, Dr. Tanya B. Dorff plays a central leadership role in the 2026 ASCO Genitourinary Cancers Symposium, steering educational programming for prostate cancer innovations. These accolades underscore the commitment of City of Hope’s faculty to shaping the future of cancer research and clinical application.

Complementing individual achievements, ten City of Hope clinicians were named among the Los Angeles Business Journal’s “Leaders of Influence: 2026 LA Top Doctors.” Specialists spanning hematology, surgical oncology, urology, endocrinology, and pediatric oncology were recognized for their outstanding clinical expertise and dedication to patient care. This cohort includes Dr. Andrew Artz, Dr. Marwan Fakih, Dr. Thomas J. Gernon, Dr. Lorena Gonzalez, and other luminaries whose diverse disciplines underscore the center’s multidisciplinary strength.

Embedded within City of Hope’s mission is a commitment to translating benchside discoveries into tangible clinical benefits. Founded more than a century ago, City of Hope has pioneered breakthroughs that have revolutionized cancer therapeutics, diabetes management, and immunology. The institution’s integrated model spans a National Cancer Institute-designated comprehensive cancer center, expansive clinical networks, and robust academic and philanthropic infrastructures, ensuring continuous progress in life-saving science.

Collectively, these advancements reflect a vibrant ecosystem at City of Hope, where multidisciplinary collaboration, technological innovation, and patient-centered research converge. By elucidating molecular underpinnings of cancer, neurodegeneration, and immune regulation, scientists are forging pathways toward precision medicine that promises to transform outcomes for some of the most challenging diseases. The integration of AI-driven analytics, stem cell technologies, and immunologic insights illustrates a forward-looking agenda poised to accelerate discoveries from the laboratory to the bedside.

Subject of Research:
Article Title:
News Publication Date:
Web References:
References:
Image Credits: City of Hope / Yanhong Shi Lab
Keywords: Cancer, Lung cancer, Stem cell research

The findings indicate that VISTA functions as an immune checkpoint molecule, which modulates the activity of immune cells in the tumor microenvironment. This modulation is facilitated by the regulation of m6A, a common RNA modification that influences gene expression and stability. Research has demonstrated that altered m6A methylation patterns can lead to significant differences in the expression of immune checkpoints like VISTA. The implications of this regulatory mechanism are profound, particularly in a disease as aggressive as NSCLC, where immune evasion is a critical characteristic of tumor growth and metastasis.

At the heart of the study is the intricate interplay between m6A methylation, VISTA expression, and the immune response orchestrated by STAT3 signaling pathways. The researchers identified that the activation of STAT3 was critical for the expression of CCL22, a chemokine that recruits and activates regulatory T cells (Tregs). Tregs play a crucial role in dampening the immune response against tumors, thus promoting an environment conducive to cancer progression. By elucidating these pathways, the researchers provide a clearer understanding of how tumors can manipulate immune responses to their advantage.

As NSCLC remains a leading cause of cancer-related mortality worldwide, the identification of VISTA as a modulator of immune responses highlights a potential target for immunotherapy. Therapies aimed at inhibiting VISTA could have significant implications for enhancing the effectiveness of existing treatments, such as checkpoint inhibitors that target PD-1/PD-L1 pathways. The ability to harness the intrinsic capabilities of the immune system to combat cancer is a cornerstone of modern oncology, and this discovery adds a new dimension to that pursuit.

Moreover, the study contributes to the ever-expanding field of epitranscriptomics, focusing on how RNA modifications influence cellular functions in health and disease. The implications of m6A modification extend beyond NSCLC, potentially impacting various malignancies and other diseases. Understanding the broader consequences of m6A methylation and its interplay with immune modulation could lead to the development of novel strategies aimed at reprogramming immune responses to combat a variety of cancers effectively.

The research also sparks critical discussions regarding the functional implications of tumor-immune interactions. It raises questions about the nature of immune cell infiltration in tumors expressing VISTA and how this expression correlates with clinical outcomes in NSCLC patients. The findings suggest that assessing VISTA levels alongside other immune checkpoints could offer insights into patient prognosis and treatment responses, paving the way for more personalized approaches to cancer therapy.

Furthermore, the investigation into the role of CCL22 in the context of NSCLC adds another layer of complexity to our understanding of tumor-immune dynamics. The ability of tumors to induce Treg accumulation through chemokines like CCL22 highlights the strategic maneuvers employed by cancer cells to escape immune detection. It beckons further exploration into the mechanisms behind Treg recruitment and the functional consequences of their presence within the tumor microenvironment, which could potentially inform future therapeutic targets.

As the study by Xu, Shen, and Jiang gains traction within the scientific community, it is likely to attract attention not only for its immediate findings but also for its overarching implications in cancer biology. The prospect of targeting VISTA and its regulatory pathways presents a tantalizing opportunity for researchers and clinicians alike. It accentuates the need for more comprehensive studies that can validate these findings in larger cohorts and different cancer types.

In conclusion, the research uncovering the role of VISTA expressed on tumor cells as a mediator of immune responses in NSCLC marks a significant advancement in the field of cancer immunology. As scientists continue to unravel the complexities of tumor-intrinsic mechanisms that facilitate immune evasion, the potential for novel therapeutic strategies expands. The integration of these findings into clinical oncology may hold the key to transforming the landscape of cancer treatment, with the hope of enhancing patient outcomes and survival rates in the battle against this devastating disease.

In an era of rapid advancements in cancer research, every discovery builds upon previous knowledge, leading to new horizons in treatment strategies. The interplay between RNA modifications like m6A, immune checkpoints such as VISTA, and the broader immune landscape underscores the complexity of the tumor microenvironment and the multifaceted approaches necessary to tackle cancer effectively. These findings not only inform ongoing research but also inspire optimism for developing innovative therapies that harness the immune system’s full potential.

The study underscores the importance of continued exploration into the regulatory mechanisms that govern immune system interactions with tumors. As researchers delve deeper into the nuances of these pathways, we may witness the emergence of new modalities that could redefine the standard of care for lung cancer patients and potentially those afflicted by other malignancies.

The evolving narrative around cancer therapy is one of collaboration, with diverse disciplines coming together to shed light on the intricacies of tumor biology. The insights gleaned from this research are crucial for driving forward the next generation of immunotherapies and biomarker development, signaling a brighter future for patients combating the realities of non-small cell lung cancer.

The implications of this research extend beyond the laboratory, offering a promise of hope to the thousands of patients battling this formidable disease. By understanding how tumors manipulate their microenvironment, researchers can better strategize and develop tailored therapies that can outsmart the cunning adaptations of cancer cells. The pursuit of innovative treatments based on this foundational research could lead to transformative changes in the treatment landscape for NSCLC.

In summary, the incisive work by Xu, Shen, Jiang, and their colleagues illuminates pathways previously shrouded in mystery within NSCLC. This is not merely an academic inquiry; it is a clarion call for further investigation into immune modulation in cancer, urging the scientific community to unite in a multifaceted approach to conquer the challenges posed by this disease. The findings serve as a beacon, guiding future research and fostering hope for improved therapeutic strategies that can ultimately save lives.

Subject of Research: The role of VISTA expressed on tumor cells in regulating the immune microenvironment in non-small cell lung cancer (NSCLC).

Article Title: VISTA expressed on tumor cells is regulated by m6A and influences immune microenvironment through STAT3/CCL22 in NSCLC.

Article References:

Xu, H., Shen, K., Jiang, B. et al. VISTA expressed on tumor cells is regulated by m6A and influences immune microenvironment through STAT3/CCL22 in NSCLC.
J Transl Med 23, 1043 (2025). https://doi.org/10.1186/s12967-025-06818-3

Image Credits: AI Generated

DOI:

Keywords: VISTA, m6A, immune microenvironment, non-small cell lung cancer, STAT3, CCL22, tumor immunology, immunotherapy.

Liver hepatocellular carcinoma is notorious for its aggressive nature and poor prognosis, primarily due to late diagnosis and limited effective treatment options. One of the hallmarks of aggressive cancers like LIHC is aerobic glycolysis—often referred to as the Warburg effect—where cancer cells preferentially generate energy through glycolysis even in the presence of adequate oxygen. This metabolic reprogramming supports rapid cancer cell proliferation and survival. However, the molecular regulators orchestrating this metabolic switch in LIHC remain incompletely understood.

The recent investigation sheds light on the role of RNA modifications in cancer metabolism, specifically focusing on 5-methylcytosine (m5C) modification, a chemical alteration of RNA that influences its stability and function. NSUN5, a member of the RNA m5C methyltransferase family, emerged as a key player. By analyzing expression data from The Cancer Genome Atlas (TCGA), the researchers discovered that both NSUN5 and EFNA3 are upregulated in LIHC and correlate strongly with poor patient survival, suggesting their contribution to tumor aggressiveness.

Mechanistically, NSUN5 was found to catalyze m5C methylation on the EFNA3 transcript. EFNA3, a gene encoding ephrin-A3, is implicated in various cellular processes including cell proliferation and migration, often hijacked during tumorigenesis. The m5C modification by NSUN5 stabilizes EFNA3 mRNA, enhancing its expression and facilitating enhanced glycolytic activity in tumor cells. This epigenetic modification essentially fuels the metabolic machinery that cancer cells rely on for growth and survival.

The research team employed a combination of in vitro and in vivo models to validate their findings. Knocking down NSUN5 in liver cancer cell lines resulted in a significant decrease in both cell viability and glycolytic activity, highlighting the enzyme’s critical role in maintaining the metabolic phenotype necessary for tumor progression. Interestingly, the suppression of NSUN5 also translated to slower tumor growth in animal xenograft models, reinforcing its tumourigenic importance.

Further molecular assays revealed a positive correlation between NSUN5 and EFNA3 expression. Notably, the overexpression of EFNA3 was able to rescue the inhibitory effects on glycolysis and cell viability caused by NSUN5 knockdown, underscoring that EFNA3 acts downstream of NSUN5’s epigenetic regulation. This finding confirms the NSUN5-m5C-EFNA3 axis as a critical pathway promoting LIHC progression.

Epitranscriptomics—the study of chemical modifications on RNA—has rapidly emerged as a frontier in understanding cancer biology. This study contributes significantly to that field by elucidating how m5C modification dynamically regulates gene expression relevant to tumor metabolism. Unlike genetic mutations, such epigenetic modifications offer a reversible means of regulating oncogenes and tumor suppressors, opening avenues for targeted therapy.

Importantly, the implication of NSUN5 in promoting glycolysis via m5C methylation of EFNA3 introduces a dual avenue for therapeutic exploitation. Targeting NSUN5 could disrupt the metabolic advantage tumor cells maintain, while simultaneously destabilizing oncogenic mRNA transcripts. Such strategies could potentially enhance the efficacy of existing treatments or lead to innovative drug designs aimed at the epitranscriptomic machinery.

Given that LIHC remains a leading cause of cancer-related mortality worldwide, largely due to limited therapeutic options, these findings inject fresh hope into the research and clinical communities. New therapeutic targets are urgently needed, especially those capable of halting cancer metabolism which fuels tumor growth and therapy resistance.

Furthermore, the findings of this study emphasize the importance of integrating RNA modification profiling in cancer diagnostics and treatment planning. Measuring NSUN5 and EFNA3 levels, alongside known biomarkers, could improve prognostic accuracy and help tailor personalized medical interventions for LIHC patients.

The study also raises intriguing questions about the broader roles of m5C modifications in other cancers and metabolic disorders. Whether NSUN5 influences other metabolic pathways or interacts with additional epigenetic regulators remain exciting topics for future research. Decoding the full spectrum of NSUN5’s targets could illuminate new principles of tumor biology.

While much work remains before these insights translate into clinical therapies, the study lays a robust foundation for drug development, including small molecule inhibitors or RNA-based therapeutics targeting the NSUN5-EFNA3 axis. Such agents could effectively ‘starve’ tumors of their glycolytic fuel source, crippling their growth capabilities.

Ultimately, this work exemplifies the power of multi-disciplinary research combining bioinformatics, molecular biology, and translational animal studies. As researchers continue to unpack the complex epigenetic networks in cancer, targeting RNA modification enzymes like NSUN5 holds considerable promise for more effective and less toxic cancer treatments.

In conclusion, the current study offers compelling evidence that NSUN5 serves as a key epitranscriptomic regulator in LIHC, accelerating tumor progression through m5C-mediated stabilization of EFNA3 and subsequent enhancement of glycolysis. These insights underscore the potential of NSUN5 as a valuable biomarker and a novel, actionable target to combat one of the most lethal cancers globally.

Subject of Research: Mechanisms by which the RNA methyltransferase NSUN5 influences glycolysis and tumor progression in liver hepatocellular carcinoma via m5C modification of EFNA3.

Article Title: NSUN5 accelerates the progression of liver hepatocellular carcinoma by m5C-EFNA3-mediated glycolysis

Article References:
Han, Y., Deng, X., Chen, H. et al. NSUN5 accelerates the progression of liver hepatocellular carcinoma by m5C-EFNA3-mediated glycolysis. BMC Cancer 25, 1237 (2025). https://doi.org/10.1186/s12885-025-14714-8

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14714-8

Colorectal cancer remains one of the leading causes of cancer-related mortality worldwide, demanding innovative molecular markers for earlier detection and more effective targeted therapies. RNA modifications, collectively termed the epitranscriptome, have recently gained acclaim for their regulatory roles in gene expression beyond the classical DNA methylation and histone modification paradigms. Among these, pseudouridine (Ψ), the most abundant RNA modification, is catalyzed by a group of enzymes known as pseudouridine synthases (PUS). Despite its recognized presence in various RNA species, the functional dynamics of Ψ in oncogenic processes, particularly in CRC, have remained largely unexplored until now.

The research team embarked on a comprehensive profiling of Ψ modifications at both bulk tissue and peripheral blood levels from CRC patients versus healthy controls. This was made possible through innovative methodologies like BID-seq and PRAISE-seq, which enable high-resolution, transcriptome-wide mapping of pseudouridine sites with unmatched specificity and sensitivity. Crucially, the study identified significantly elevated Ψ modifications in critical oncogenes within CRC tissues, with these modifications correlating robustly with established clinical biomarkers such as alpha-fetoprotein (AFP) and cancer antigen 125 (CA125). This correlation not only underscores the biological relevance of Ψ but also suggests its potential as a minimally invasive diagnostic marker when detected in circulating blood.

A focal point of the study lies in elucidating the role of the enzyme Dyskerin pseudouridine synthase 1 (DKC1), a pivotal member of the PUS family that governs Ψ site installation in RNA. Previous literature has noted DKC1 overexpression in various cancers, but its functional consequences in CRC remained ambiguous. This investigation confirms that DKC1 is markedly upregulated in CRC tissues, where it binds selectively to the 3′ untranslated regions (3′ UTRs) of ribosomal protein mRNAs, notably stabilizing these transcripts. Such stabilization amplifies ribosomal protein synthesis, fueling unchecked cellular proliferation—a hallmark of malignancy.

Notably, the study explores pharmacological interventions targeting DKC1, revealing that Pyrazofurin, a specific inhibitor of DKC1’s pseudouridine synthase activity, effectively diminishes Ψ levels. This reduction translates into decreased ribosomal protein expression and, more significantly, potent suppression of tumor growth in xenograft mouse models. These findings offer compelling evidence of DKC1’s therapeutic potential, highlighting RNA modification enzymes as promising drug targets in CRC treatment paradigms.

Beyond DKC1, the research expanded its investigative horizon to other PUS family members, specifically PUS7 and PUS10. While their precise mechanistic roles require further elucidation, observed correlations between their expression levels and global Ψ modification patterns suggest these enzymes collectively orchestrate Ψ dynamics within the CRC transcriptome. Such multiplicity in regulation implies a complex epitranscriptomic network governing tumor biology, inviting comprehensive studies into the functional interplay among PUS enzymes.

Genome-wide analyses unveiled that ribosomal protein RPL19 stands out as an oncogenic locus where both transcriptional upregulation and enhanced Ψ modification converge. This dual modulation hints at a synergistic mechanism whereby pseudouridylation may augment transcript stability or translation efficiency, subsequently driving malignant transformation. Moreover, the study uncovered distinct disparities in Ψ profiles when comparing tumor to adjacent normal tissues, with these differences aligning closely to clinical markers such as CA153 and CA199, thereby reinforcing the diagnostic relevance of RNA pseudouridylation.

Remarkably, the investigators extended their profiling to small nucleolar RNAs (snoRNAs), known guides of RNA modifications but seldom implicated directly in cancer diagnostics. The identification of differential Ψ modifications within snoRNAs in CRC suggests these non-coding RNAs might serve as novel biomarkers, expanding the landscape of epitranscriptomic contributors and potential targets in CRC pathology. This extension into the non-coding RNA realm propels a paradigm shift, emphasizing the multifaceted layers of RNA regulation in oncogenesis.

The correlation between peripheral blood Ψ modification patterns and tumor tissue profiles carries profound clinical implications. Blood-based Ψ signatures exhibited partial consistency with tumoral datasets and aligned with standard hematologic indicators such as white blood cell count (WBC) and AFP levels. This discovery highlights the practical potential for developing non-invasive blood tests that monitor CRC progression or response to therapy through epitranscriptomic markers, circumventing the need for invasive biopsy procedures.

From a mechanistic standpoint, these findings illuminate the pivotal role of epitranscriptomic regulation in modulating not just RNA stability but also the broader translational landscape within cancer cells. The dynamic addition of pseudouridine modulates RNA structure and function, influencing ribosome biogenesis, mRNA translation fidelity, and potentially the immune system’s recognition of tumor cells. Such multifarious roles position pseudouridylation as a central nexus in cancer biology.

This research opens new frontiers in RNA biology by charting a definitive molecular framework wherein distinct pseudouridylation signatures serve dual purposes: assisting in precise molecular stratification of CRC patients and enabling the design of targeted therapeutic interventions disrupting these epitranscriptomic modifications. The advent of small molecule inhibitors like Pyrazofurin offers a testament to the translational power of these discoveries, foreshadowing the emergence of epitranscriptomic modulators as a novel class of anticancer agents.

The integration of cutting-edge RNA sequencing technologies, sophisticated biochemical assays, and clinically relevant sample analyses exemplifies a holistic approach that vividly captures the complexity and clinical utility of RNA modifications. By bridging the molecular intricacies of pseudouridylation with tangible diagnostic and therapeutic applications, this study marks a watershed moment in cancer research, emphasizing the indispensability of RNA epigenetics in the future of precision oncology.

In conclusion, this comprehensive study elucidates the hitherto underappreciated significance of RNA pseudouridylation in colorectal cancer. It establishes a foundational understanding for how alterations in RNA modification landscapes contribute to tumorigenesis and opens innovative paths toward exploiting these modifications for clinical benefit. The findings champion RNA pseudouridine as both a biomarker and a therapeutic target, heralding an exciting era where epitranscriptomic insights translate seamlessly into improved patient outcomes.

Subject of Research: RNA pseudouridine modification profiling and functional characterization in colorectal cancer

Article Title: Unveiling the Clinical Significance of RNA Pseudouridine in Colorectal Cancer

News Publication Date: 2024

Web References: DOI: 10.1007/s11427-024-2743-y

Keywords: colorectal cancer, RNA pseudouridine, DKC1, pseudouridine synthase, RNA modification, epitranscriptomics, BID-seq, PRAISE-seq, ribosomal proteins, Pyrazofurin, diagnostic biomarkers, non-invasive diagnosis