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| The Hallmarks of Cancer: 25 years guiding discovery and therapy |
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| Twenty-five years after its publication, the Hallmarks of Cancer framework continues to illuminate tumor biology and drive therapeutic innovation. This special issue surveys how the concept has shaped our understanding of cancer, guided drug development, and evolved to incorporate new discoveries and address emerging challenges. |
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| Shared leadership, shared responsibility |
| Zoë S. Walters, Timothy J. Underwood |
| In choosing to merge two independent teams, we stepped into an unconventional model of co-leadership that reshaped our scientific lives. A clinician and a scientist leading together challenged academic norms, dissolved the loneliness of traditional principal investigator roles, and created a shared patient-centered vision for translational research. By embedding patients, carers, and high-performance coaching at our core, we built a culture defined not by individual burden but by collective responsibility, sustainability, and genuine collaboration. This is our story. |
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| Hallmarks of Cancer: How did it inspire you? |
| Lucas T. Jae, Lillian L. Siu, Lei Zhang, Anwesha Dey, Lisa M. Coussens, Gerard Evan |
| In this Voices piece, we asked researchers to reflect on how the Hallmarks of Cancer have shaped their career paths, their research directions, and their broader perspectives on cancer. Their reflections show how the framework continues to guide discovery, encourage collaboration across disciplines, and inspire new ways to better understand and treat cancer. |
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| Hallmarks of setting up a successful patient advocacy group |
| Andrea Anampa-Guzmán, Patrick McGuire, Fiorella S. Gagliardi, Yi Lin Teh, Karen Nakala, Dozie Akwarandu |
| Patient advocacy has the potential to contribute to effective cancer care with real-world impact, regardless of a country’s socioeconomic status. Here, we asked representatives of patient advocacy groups for key considerations to overcome challenges when starting out in resource-limited settings. We are grateful to them for sharing their voices and for their relentless fight toward making cancer care more accessible. |
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| Hallmarks of cancer research: Enabling transformative discovery through global team science |
| Rebecca L. Eccles, Gabriela Carreno, Lorenzo de la Rica, Andrew Kurtz, Dinah S. Singer, David Scott |
| Since the original Hallmarks of Cancer, our understanding of the complexity of the disease has expanded dramatically. Researching cancer is no longer simply a question of ever more sophisticated experiments but of delivering science in an evolving and complex system. Here, we discuss how to support global team science and catalyze transformative discovery, drawing on our experience from the Cancer Grand Challenges initiative. |
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| Improving immunotherapy in solid tumors using FMT |
| Diwakar Davar, Hassane M. Zarour, Georgio Trinchieri |
| Recent clinical trials demonstrate that fecal microbiota transplantation (FMT) enhances first-line immune checkpoint inhibitor efficacy in renal cell carcinoma, cutaneous melanoma, and non-small cell lung cancer with acceptable safety. Benefit appears mediated by functional microbiome remodeling, depletion of deleterious taxa, and systemic immunometabolic modulation, supporting microbiome-directed therapeutic strategies for cancer immunotherapy. |
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| Tackling the complexity of cancer with generative models |
| Ashley Mae Conard, Madeline Hughes, James Hall, Neil Tenenholtz, Eric Zimmermann, Lorin Crawford, Ava P. Amini, Kristen Severson |
| Open Access |
| This perspective summarizes the ways in which artificial intelligence has already impacted cancer detection, understanding, and intervention, then posits that generative models are a key technology for further advances of computational methods for capturing cancer’s complexity. |
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| Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers |
| Mengyao Shi, Gary J. Patti, Marc J. Gunter, Ramaswamy Govindan, Iris Lansdorp-Vogelaar, Ting Wang, Jeffrey P. Townsend, Graham A. Colditz, Yasmine Belkaid, Yin Cao |
| Open Access |
| Rising early-onset cancers challenge existing frameworks for understanding and managing cancer. This perspective outlines a roadmap for addressing this challenge by advancing the discovery of cancer causes, cancer risk assessment, and cancer preventability characterization. |
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| Hallmarks of cancer—Then and now, and beyond |
| Douglas Hanahan |
| Open Access |
| Hanahan revisits the evolving framework of cancer hallmarks, synthesizing 25 years of conceptual refinement into a multidimensional view of tumor biology. This review highlights how aberrant capabilities, enabling traits, microenvironmental players, and systemic interactions converge to drive tumorigenesis and proposes that mechanism-guided co-targeting of hallmarks may offer promising therapeutic strategies. |
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| Targeting genomic instability in cancer |
| Timothy A. Yap, H. Charles Manning, Puja Sapra, Gordon B. Mills, Mark J. O’Connor |
| Genomic instability, a hallmark of cancer, has been targeted by treatments from chemotherapy and radiation to PARP inhibitors for repair-deficient tumors, and more recently to antibody-drug conjugates and radiopharmaceuticals. Precision medicine targeting genomic instability now emphasizes patient selection and rational drug combinations, expanding the therapeutic index for better outcomes. |
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| A recipe for chaos: Extrachromosomal DNA and the hallmarks of cancer |
| Ivy Tsz-Lo Wong, Chris Bailey, Sihan Wu, Anton G. Henssen, Benjamin F. Cravatt, Zhijian J. Chen, Vineet Bafna, Mariam Jamal-Hanjani, Charlie Swanton, Howard Y. Chang, Paul S. Mischel |
| Open Access |
| When oncogenic genetic elements untether from chromosomes and no longer follow Mendelian inheritance, genomic chaos and accelerated evolution ensues. In this review, Wong et al. discuss the mechanistic basis and impact of extrachromosomal DNA (ecDNA) and how it enables many of the Hallmarks of Cancer. |
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| Cell death in cancer |
| Marcus Conrad, Andreas Strasser, Philipp J. Jost, Junying Yuan, Feng Shao, Peter Vandenabeele, Adam Wahida |
| Open Access |
| The expanding landscape of cell death programs has transformed cancer biology and opened exciting therapeutic frontiers. This review maps how these pathways drive cancer progression and therapy response and highlights future directions to overcome resistance to cancer cell death and immune suppression. |
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| Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise |
| Clemens Hinterleitner, Hailey V. Goldberg, Domhnall McHugh, Valentin J.A. Barthet, Aveline Filliol, Scott W. Lowe |
| Cellular senescence, defined by six major hallmarks, is a program that halts cell division while rewiring chromatin, metabolism, microenvironment sensing, and immune interactions to either suppress or promote cancer and is an exciting frontier for precision therapy. |
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| Targeting angiogenesis: Lessons from 25 years of normalizing tumor vasculature |
| Sonu Subudhi, Somin Lee, Rakesh K. Jain |
| Open Access |
| We review the evolving narrative of targeting angiogenesis from starving tumors to vascular normalization as a therapeutic principle and highlight recent spatial-omics revelations and the emerging role of neural, microbial, hormonal, and chronological factors. |
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| Mapping intratumor heterogeneity across layers for advancing immunotherapy |
| Jean-Christophe Marine, Osnat Bartok, Shira Sagie, Pietro Paolo Vitiello, Alberto Bardelli, Chen Weller, Tian-Gen Chang, Claudia Tonelli, Stefani Spranger, Eytan Ruppin, Yardena Samuels |
| Open Access |
| Multi-layer intratumor heterogeneity shapes tumor immunity and therapeutic response across cancer types. This review highlights the importance of integrating intratumor heterogeneity across layers for guiding next-generation immunotherapy strategies. |
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| Cancer ecosystems: A dynamic interplay across scales |
| Daniela F. Quail, Johanna A. Joyce |
| Open Access |
| Cancer does not evolve in isolation but rather within complex ecosystems that operate across spatial, temporal, and systemic scales. Within the tumor microenvironment, diverse cell populations assemble into specialized niches continually reshaped by systemic physiology, environmental inputs, and therapeutic pressure. Quail and Joyce propose a multi-scale framework that reframes therapeutic strategies from targeting maligant cells alone to reprogramming the cellular, vascular, and systemic networks that sustain disease, charting a path toward durable and curative precision oncology. |
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| Cancer neuroscience: The past, the present, and the road ahead |
| Frank Winkler, Sophie Heuer, Ferdinand Althammer, Hellmut Augustin, Filippo Beleggia, Ihsan Ekin Demir, Julian Koenig, Rohini Kuner, Thomas Kuner, Sonja Loges, Michael Platten, Hans Christian Reinhardt, Judith M. Rich, Felix Sahm, Ruth Martha Stassart, Vera Thiel, Andreas Trumpp, Varun Venkataramani, Wolfgang Wick, Matthia A. Karreman |
| Open Access |
| The multilayer crosstalk between cancer and the nervous system not only shapes cancer development but also influences systemic human physiology that governs patient outcomes. This review outlines overarching principles guiding future development of cancer neuroscience, paving the way for improving disease control and quality of life. |
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| Hallmarks of liver cancer: Therapeutic implications |
| Josep M. Llovet, Roser Pinyol, Silvia Affo, Mark Yarchoan, Gregory J. Gores, Robin Kate Kelley, Scott W. Lowe, Daniela Sia, Augusto Villanueva |
| Open Access |
| Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are driven by distinct cancer hallmarks that shape their biology, therapeutic vulnerabilities, and immune interactions. This review explores how this framework has reshaped our understanding of molecular mechanisms and immunotherapy responses, as well as advanced precision medicine in liver cancer. |
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