Trends in Cancer

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RNA vaccines for cancer: revolutionizing immunization strategies Cancer vaccines have emerged as a promising strategy in cancer immunotherapy, capable of eliciting robust antitumor immune responses by targeting tumor-associated antigens or tumor-specific antigens. Among the various vaccine platforms, RNA-based vaccines have garnered substantial attention, especially in light of the success of mRNA vaccines during the COVID-19 pandemic. This review outlines the fundamental characteristics of different RNA vaccine modalities, summarizes recent clinical applications in cancer treatment, and highlights strategies aimed at improving their efficacy and safety. Furthermore, we discuss the current challenges facing RNA vaccine development and offer perspectives on future directions in this rapidly advancing field.

RNA vaccines for cancer: revolutionizing immunization strategies

Advancing human leukocyte antigen-based cancer immunotherapy: from personalized to broad-spectrum strategies for genetically heterogeneous populations Human leukocyte antigen (HLA)-based immunotherapeutics, such as tebentafusp-tebn and afamitresgene autoleucel, have expanded the treatment options for HLA-A*02-positive patients with rare solid tumors such as uveal melanoma, synovial sarcoma, and myxoid liposarcoma. Unfortunately, many patients of European, Latino/Hispanic, African, Asian, and Native American ancestry who carry non-HLA-A*02 alleles remain largely ineligible for most current HLA-based immunotherapies. This comprehensive review introduces HLA allotype-driven cancer health disparities (HACHD) as an emerging research focus, and examines how past and current HLA-targeted immunotherapeutic strategies may have inadvertently contributed to cancer health disparities. We discuss several preclinical and clinical strategies, including the incorporation of artificial intelligence (AI), to address HACHD. Last, we emphasize the urgent need for further research to better understand HLA allotype heterogeneity and its influence on tumor immunopeptidome-driven immune responses. We anticipate that these strategies will accelerate the development and implementation of both personalized and broad-spectrum HLA-based immunotherapies, and will ultimately improve cancer treatment across genetically heterogeneous patient populations worldwide.

Advancing human leukocyte antigen-based cancer immunotherapy: from personalized to broad-spectrum strategies for genetically heterogeneous populations

Reprogramming T cell stemness against cancer Stem-like CD8+ T cells – characterized by high-level expression of the transcription factor TCF-1, and known as progenitor exhausted T (Tpex) cells – have emerged as crucial mediators of durable antitumor immunity. These cells demonstrate unique self-renewal capacity, multipotency, and enhanced responsiveness to immune checkpoint blockade therapy. This review synthesizes current understanding of Tpex cell biology, including their defining characteristics, tissue distribution, and functional importance in antitumor immunity. We focus particularly on innovative approaches to preserve and enhance T cell stemness through combination therapies, cytokine signal modulation, epigenetic regulation, tumor microenvironment modification, and microbiota-based interventions. The development of these next-generation immunotherapies targeting T cell stemness represents a transformative frontier in oncology, holding significant promise for improving therapeutic outcomes in cancer patients.

Reprogramming T cell stemness against cancer

Spatially resolving cancer: from cell states to therapy Recent advances in spatial multi-omics technologies and analytical methods are transforming our understanding of how cancer cells and their microenvironments interact to drive critical processes such as lineage plasticity, immune evasion, and therapeutic resistance. By linking cancer cell states, lineage plasticity, clonal dynamics, oncogenic pathways, and cellular interactions to their spatial context, these innovations provide deep biological insights and reveal clinically relevant molecular programs and spatial biomarkers. This review highlights key breakthroughs in spatial profiling and computational approaches, including integration with computational pathology, multimodal data, and machine learning to uncover important biological insights. We discuss challenges in spatial multimodal data integration and emerging clinical applications, and we propose a roadmap to accelerate clinical translation and advance precision oncology through spatially resolved, actionable, molecular insights.

Spatially resolving cancer: from cell states to therapy

How structural variation shapes the cancer epigenome It is widely recognized that cancer develops through a series of changes that modify the genomes of normal cells, enabling them to acquire new malignant properties. Epigenetic disruptions, which do not directly change the genetic sequence but rather influence how the genome is interpreted, have garnered significant attention as contributors to malignant transformation and progression. With the advent of new technologies to profile both the genome and epigenome of cancer cells simultaneously, the interplay between structural variation (SV) and epigenetic changes in malignancy is now an expanding field. In this review, we describe the key technological advances and highlight recent research exploring the relationship between SV and the epigenome in cancer.

How structural variation shapes the cancer epigenome

Canonical and non-canonical intricacies of MCL-1 in cancer Myeloid cell leukemia 1 (MCL-1), an antiapoptotic protein, belongs to the BCL-2 protein family and is an extensively studied anticancer target. MCL-1 inhibitors have been in development for decades but fall short on efficacy, toxicity, and side-effects. Recently, Brinkmann et al. shed light on the apoptosis-unrelated function of MCL-1 and its physiological role that could critically lead to MCL-1 inhibitor development.

Canonical and non-canonical intricacies of MCL-1 in cancer

Viral mimicry in cancer therapy Viral mimicry is a cellular state in which the reactivation of silenced transposable elements (TEs) leads to the accumulation of immunogenic nucleic acids, triggering innate immune pathways that resemble responses mounted against viral pathogens. Although they were first characterized in the context of epigenetic therapies, growing evidence indicates that other cancer treatment modalities – including radiotherapy, chemotherapies, and targeted therapies – can also induce TE reactivation and viral mimicry responses in cancer cells. This review synthesizes the current knowledge on treatment-induced TE-mediated immune responses in cancer, highlighting therapeutic strategies, shared and distinct molecular mechanisms, and their broader implications for tumor–immune interactions and treatment outcomes.

Viral mimicry in cancer therapy

CAR T cell persistence in cancer Chimeric antigen receptor T cell (CAR T) therapies are ‘living drugs’ in which T cells are genetically engineered to recognize and kill cancer cells. A major barrier to progress for CAR T targeting liquid and solid tumors is the poor persistence of these cells in vivo, which limits therapeutic efficacy. In this review, we summarize the field’s current understanding of CAR T persistence, including clinical observations, patient correlatives and multiomics approaches, and emerging cell engineering and manufacturing strategies. We also propose a conceptual framework for CAR T persistence to guide interpretation of clinical data and the design of more potent and efficacious CAR T therapeutics.

CAR T cell persistence in cancer

CX3CL1: a key switch of cell death immunogenicity CX3CL1 (fractalkine) is a unique chemokine with dual roles in cancer biology, capable of exerting both tumor-promoting and tumor-suppressive effects. Acting through its receptor CX3CR1, CX3CL1 facilitates immune evasion, angiogenesis, metastasis, and tumor cell survival and proliferation by recruiting immunosuppressive myeloid-derived suppressor cells. Conversely, it can enhance antitumor immunity by attracting cytotoxic T lymphocytes, natural killer cells, and dendritic cells into the tumor microenvironment. CX3CL1 has also been implicated in promoting immunogenic cell death–induced anticancer immune responses. However, excessive expression of CX3CL1 may paradoxically suppress immune activation, highlighting the importance of dose and context in its application. CX3CL1-based gene or mRNA therapies, particularly in combination with immune checkpoint inhibitors, show promising potential for cancer treatment.

CX3CL1: a key switch of cell death immunogenicity

Optimizing mitochondria function in immune cells: implications for cancer immunotherapy The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.

Optimizing mitochondria function in immune cells: implications for cancer immunotherapy

Fueling the revolution: RIBOTACs manipulating RNA decay Ribonuclease-targeting chimeras (RIBOTACs) are innovative RNA-targeting molecules that combine small-molecule RNA binders with endogenous RNase L-recruiting moieties, enabling catalytic degradation of previously considered 'undruggable' transcripts. The unique mechanism of RIBOTACs allows them to circumvent limitations of existing RNA-targeted therapeutics, expanding their therapeutic potential in oncology.

Fueling the revolution: RIBOTACs manipulating RNA decay

The emerging roles of the urea cycle in tumor microenvironment and therapies The urea cycle (UC) is a vital metabolic pathway that is responsible for the disposal of nitrogen and the production of metabolites necessary for biosynthesis. UC dysregulation is common in various cancers and impacts on cellular metabolism and the tumor microenvironment (TME). In this review we explore alterations in the expression of UC genes and metabolites in tumors, focusing on their roles in tumor progression, the TME, and cancer therapies. We discuss the effects of the UC on immune responses involving T cells and immunosuppressive cells, as well as on stromal cells and angiogenesis. We highlight the impact of arginine and polyamine metabolism in the TME. Although therapeutic strategies targeting the UC show promise, including arginine deprivation therapy (ADT), they face challenges such as drug resistance and toxicity. It will be essential to elucidate the specific functions of UC enzymes in tumorigenesis to devise more effective, personalized tumor therapies. Future studies should focus on combination therapies and personalized medicine to improve efficacy and patient prognosis.

The emerging roles of the urea cycle in tumor microenvironment and therapies

Overcoming solid-tumor barriers: armored CAR-T cell therapy Chimeric antigen receptor (CAR)-T cell therapy has shown significant clinical benefit in hematologic malignancies but remains less effective in solid tumors due to multiple barriers, including limited tumor infiltration, immunosuppressive microenvironments, and heterogeneity or imperfect specificity in tumor-antigen expression. ‘Armoring’ CAR-T cells to express chemokine receptors, enzymes that degrade extracellular matrix components, proinflammatory cytokines, or factors that modulate immunosuppressive signals could empower CAR-T cells to overcome barriers associated with solid tumors. However, translating promising preclinical results into reliable clinical benefit for patients with solid tumors remains challenging. This review critically examines emerging CAR-T cell armoring approaches and highlights key translational hurdles and the need for innovations in human-relevant disease models, safety designs, and treatment strategies for effective translation.

Overcoming solid-tumor barriers: armored CAR-T cell therapy

Host and microbiome lipid metabolism in colorectal cancer development and therapy Colorectal cancer (CRC) remains one of the most prevalent cancers, with treatment largely dependent on surgery and chemotherapy, underscoring the need for novel or adjunct therapies. Cancer cells reprogram their lipid metabolism to support proliferation, invasiveness, and chemoresistance, making it a promising therapeutic target. Although several inhibitors of lipogenesis, lipases, lipid uptake, and lipid storage are under investigation in CRC, none have yet shown sufficient efficacy. Importantly, the tumor microenvironment (TME) and the microbiome influence CRC lipid metabolism by supplying compensatory lipids and engaging in crosstalk that affects the efficacy of lipid-targeting therapies. This review describes the role of lipids in CRC and explores how the TME and the gut/tumor microbiome may contribute to current challenges in the development of effective lipid-targeting therapies.

Host and microbiome lipid metabolism in colorectal cancer development and therapy

γδT cells and breast cancer: wicked allies Metastatic disease and therapy resistance pose significant challenges in the treatment of breast cancer. Recent studies by Rozalén et al. and Petroni et al. uncover a crucial role for IL-17A-producing γδT cells in liver metastasis and therapeutic resistance, offering new insights into the mechanisms underlying these processes.

γδT cells and breast cancer: wicked allies

Glucose restriction: double edged sword in cancer treatment Glucose restriction generally limits tumor growth. Recently, Wu et al. reported that glucose restriction inhibits primary tumors but promotes lung metastasis by forming a macrophage-dominated, natural killer (NK) cell-deficient pre-metastatic niche (PMN). This finding provides a new perspective on understanding the dual role of glucose metabolism regulation in cancer treatment.

Glucose restriction: double edged sword in cancer treatment

Excited to share our discovery of potent TRIM21 molecular glues with anticancer activity, online today @CD_AACR: "Defining the antitumor mechanism of action of a clinical-stage compound as a selective degrader of the nuclear pore complex". 1/18

How can we reawaken the body’s own anti-viral defenses to fight brain cancer?

Delighted to share our new study where we now answer this question, led by the brilliant @alvarezprado.bsky.social who is now an independent PI at LIH Luxembourg 👏👏

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www.sciencedirect.com/science/arti...

Aberrant coupling of glutamate and tyrosine kinase receptors enables neuronal control of brain-tumor growth Anastasaki and colleagues establish a previously unknown glutamate growth dependency in pediatric low-grade brain tumors (gliomas). Glioma cells hijack normal neuron-glial molecular circuits present d...

Exciting news! Our new paper is out in Neuron! We discovered how neurons drive brain tumor growth through aberrant glutamate–tyrosine kinase signaling, uncovering novel mechanisms that shape tumor progression. Grateful to our team & collaborators for making this breakthrough possible! 🧠✨

We are proud to present a Special Issue on Cancer Neuroscience, curated by editors Bennie Babayan & Ted Dobie. This issue offers a snapshot of the field through a collection of Perspectives, Reviews, and NeuroViews: cell.com/neuron/issue.... See below for details on the pieces:

Polo-like kinases as immune modulators: a new frontier in cancer immunotherapy Cancer immunotherapy has transformed treatment but faces challenges such as immune evasion and toxicity. Polo-like kinases (PLKs), frequently dysregulated in tumors, are emerging as key immune modulators. Combining PLK inhibition with immunotherapy may overcome resistance, enhance antitumor responses, and improve clinical outcomes, offering an optimally efficient strategy for cancer treatment.

Polo-like kinases as immune modulators: a new frontier in cancer immunotherapy

Immune correlates and mechanisms of TIL therapy efficacy: current insights and knowledge gaps Tumor-infiltrating lymphocyte (TIL) therapy has emerged as a transformative approach in cancer immunotherapy, particularly following the recent US Food and Drug Administration (FDA) approval of lifileucel for advanced melanoma. This review synthesizes current insights into the immune correlates and mechanisms underlying the efficacy of TIL therapy, highlighting the pivotal role of tumor immunogenicity, TIL functional states, and the tumor microenvironment (TME). Recent advances in single-cell profiling and biomarker discovery have enabled more precise patient selection and therapy optimization, while novel expansion protocols and engineered TILs are addressing resistance and broadening applicability to non-melanoma tumors. Collectively, these developments underscore the promise of next-generation TIL therapies to revolutionize treatment paradigms across a wider spectrum of solid cancers.

Immune correlates and mechanisms of TIL therapy efficacy: current insights and knowledge gaps

Reawakening retrotransposons: immune modulation in normal and malignant hematopoiesis Retrotransposons are mobile repetitive elements that constitute around 43% of the human genome. Normally silenced through epigenetic mechanisms, retrotransposons can become reactivated in response to various stimuli, producing immunogenic DNA, RNA, and peptides that trigger innate and adaptive immune responses. In normal hematopoiesis, retrotransposon reactivation can drive inflammatory signaling responses, which support stem cell activity, influencing hematopoietic stem and progenitor cell (HSPC) regeneration. In hematological cancers, their reactivation can alter the tumor microenvironment and promote immune evasion. Here, we highlight the complex interactions between retrotransposons, hematopoiesis, and immune modulation. We also emphasize the therapeutic potential of targeting retrotransposons, while addressing critical knowledge gaps in retrotransposon-driven immune modulation across both health and disease.

Reawakening retrotransposons: immune modulation in normal and malignant hematopoiesis

CRISPR tools for T cells: targeting the genome, epigenome, and transcriptome T cell therapy has curative potential for many cancers. Despite impressive clinical efficacy in hematological malignancies, current T cell therapy still faces challenges related to sustaining responses, antigen escape, cytotoxicity, limited accessibility, and difficulties in treating solid tumors. The advent of CRISPR (clustered regularly interspaced short palindromic repeats) technologies provides a promising solution to these challenges. CRISPR technologies have grown from merely tools for gene knockout to sophisticated tools that can engineer cells at various levels of the genome, epigenome, and transcriptome. In this review we discuss recent technological advancements and how their application to T cells has the potential to steer the next generation of cellular therapy. We highlight emerging applications and current technological limitations that future tool development aims to overcome.

CRISPR tools for T cells: targeting the genome, epigenome, and transcriptome

Leveraging phagocytosis using nanomedicines for cancer immunotherapy Phagocytosis upregulation plays a crucial role in bridging to adaptive immunity for cancer immunotherapy. However, current approaches to modulating phagocytosis are beneficial to certain types of cancer only. In this Forum paper, we will highlight how nanoengineering can overcome the current limitation of phagocytosis-mediated cancer immunotherapy.

Leveraging phagocytosis using nanomedicines for cancer immunotherapy

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy - Nature Perineural invasion and cancer-induced nerve injury of tumour-associated nerves are associated with poor response to anti-PD-1 therapy, which can be reversed by combining anti-PD-1 therapy with a...

Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy www.nature.com/articles/s41...

Clinical perspective and treatment of immune-related colitis after cancer immunotherapy Targeting negative regulators of immunity with immune-checkpoint inhibitors (ICIs) has led to significant survival benefit in patients with various cancer entities. ICI therapy disrupts mechanisms of immune tolerance, which induces inflammatory toxicities in different target organs, summarized as immune-related adverse events (irAEs) in some patients. ICI-colitis relies on the activation of intestinal tissue-resident memory T cells (TRM cells) and is one of the most frequently observed immune-related toxicities; it can be fatal if untreated. The disease is associated with highly cytotoxic intestinal T cells and inflammatory myeloid activation. Current clinical management relies on broad immunosuppression, potentially reducing antitumor immunity. Ideal future therapies for irAEs will uncouple immunosuppressive activities in the inflamed target organ and the tumor microenvironment.

Clinical perspective and treatment of immune-related colitis after cancer immunotherapy

CGRP-mediated neural addiction in tumor dynamic remodeling Neuro–tumor crosstalk is reshaping our understanding of cancer. Increasing data demonstrate that calcitonin gene-related peptide (CGRP) is a key neural driver of tumor growth, immune suppression, and cancer-associated symptoms, positioning CGRP-mediated neural addiction as a promising therapeutic target to disrupt tumor–nerve interactions and improve outcomes in patients with cancer.

CGRP-mediated neural addiction in tumor dynamic remodeling

Illuminating cancer therapy via cryptic antigens A recent study in Science by Ely et al. identifies immunogenic, cancer-restricted noncanonical HLA-I-bound peptides (ncHLAp) in pancreatic cancer. Using a translation-informed filtering strategy, the study uncovers cryptic antigens derived from unannotated ORFs and validate antigen-specific T cell receptors (TCRs) capable of targeting pancreatic ductal adenocarcinoma (PDAC) in preclinical models, offering new avenues for immunotherapy.

Illuminating cancer therapy via cryptic antigens