Twenty-five years after Douglas Hanahan and Robert Weinberg defined the Hallmarks of Cancer and placed “evasion of apoptosis” among the core traits of malignancy, the picture of how tumors live and die has expanded far beyond a single death program. In a new review published in Cell, Prof. Marcus Conrad and Dr. Adam Wahida of Helmholtz Munich, together with international colleagues, take stock of that expansion and lay out how the diversity of regulated cell death pathways can serve as a basis for more targeted, personalized cancer therapies.
The review appears at the start of the AACR Annual Meeting 2026 in San Diego (April 17–22), where regulated cell death and its therapeutic exploitation are among the central themes of this year’s program.
From One Death Program to Many
Apoptosis remains the death program through which most chemotherapies and radiotherapy ultimately act. But over the past two decades, researchers have shown that cancer cells can engage – and evade – a broader repertoire of regulated death modalities, including necroptosis, pyroptosis, and ferroptosis. The review brings these pathways into a single framework and shows how each is co-opted by tumors to survive treatment, shape their microenvironment, and influence immune responses.
“Tumors aren’t just avoiding apoptosis,” says Conrad. “They are actively manipulating multiple death pathways to survive and to influence their surroundings. Some forms of cell death trigger inflammation that changes how immune cells interact with the tumor, creating a supportive microenvironment.”
Ferroptosis – an iron-dependent form of cell death driven by the oxidation of membrane lipids – illustrates the point. Unlike apoptosis, it has no single molecular trigger but emerges when a cell’s iron, lipid, and redox balance is disturbed.
“Because ferroptosis is so context-dependent, it can be a very precise target,” Wahida notes. “Triggering it in the right tumor cells could kill them while engaging the immune system in a constructive way.”
A Roadmap for Precision Oncology
The authors argue that restoring the ability of cancer cells to die remains one of the most powerful strategies in oncology – but that the era of broadly toxic agents is giving way to one in which specific death programs are matched to specific tumor vulnerabilities. The same cell may resist one form of death while remaining acutely susceptible to another, whether the relevant weakness lies in metabolism, persistence under drug pressure, or metastatic capacity.
“By tailoring treatment to these vulnerabilities, we can make therapies more effective and reduce side effects,” Wahida says. “It is a way of working with the biology of the tumor rather than attacking it blindly.”
The Next 25 Years
Looking ahead, the authors anticipate that a deeper understanding of regulated cell death will reshape cancer therapy over the next quarter century, much as the original Hallmarks framework did. They envisage treatments that target tumors based on their specific weaknesses – metastatic potential, drug tolerance, metabolic adaptation, or cell-state plasticity – and that adapt as tumors evolve.
“Combining cell death biology with personalized medicine will shift the paradigm,” Conrad says. “Instead of broadly toxic treatments, we can precisely trigger the right type of cell death in each patient’s tumor.” Wahida adds: “Sydney Brenner once said that our bodies are made of cells that live, and just as surely, of cells that must die. Cancer disrupts that balance, and our challenge is to restore it safely and precisely.”
About the scientists
Prof. Marcus Conrad is Director of the Institute of Metabolism and Cell Death at Helmholtz Munich and a Professor at the Technical University of Munich (TUM). His group is a pioneer in ferroptosis research, with a focus on therapies for cancer and neurodegenerative disease.
Dr. Adam Wahida is a Senior Researcher at the Institute of Metabolism and Cell Death at Helmholtz Munich and at Harvard University.
Original publication
Conrad M, Strasser A, Jost PJ, Yuan J, Shao F, Vandenabeele P, Wahida A, 2026: Cell death in cancer. Cell. DOI: 10.1016/j.cell.2026.03.024
