On February 11, 2025, the Editorial Office of Ageing and Cancer Research & Treatment (ACRT) had the privilege of interviewing Professor Guido Kroemer, a world-renowned expert in aging and cancer research from Université de Paris Cité, France. As a distinguished member of ACRT's Editorial Board, Prof. Kroemer shared valuable insights into his groundbreaking work on autophagy, immunogenic cell death (ICD), and cancer immunotherapy. This interview marks the launch of ACRT's new Interview Column, aimed at fostering global scientific dialogue and knowledge exchange.

About Prof. Guido Kroemer

• Fellow of the European Academy of Sciences
• President of the European Academy of Tumor Immunology (EATI)
• President-elect of the European Network for Cancer Immunotherapy (ENCI)
• Director of the metabolomics and cell biology platforms at Gustave Roussy and of the Inserm "Metabolism, Cancer and Immunity" team
• Professor at the Faculty of Medicine of Paris-Descartes University
• Honorary Professor at the Suzhou Center of Systems Medicine
• Editorial Board member of ACRT

Prof. Kroemer is renowned for his transformative contributions to cell biology and cancer research, particularly in mitochondrial control of cell death, the anti-aging role of autophagy, and immune responses that enhance anticancer therapies. His exceptional work has earned numerous honors, including the International Prize "Lombardy & Research" (2019), a Cancer Research ASPIRE Award from the Mark Foundation (2021), and the European Research Council (ERC) Advanced Investigator Award (2023).

The following are the details of the interview:

Q1. What initially sparked your interest in aging, particularly in the context of autophagy and cell death?

Guido Kroemer: At the beginning of the 21st century, we were still believing that autophagy would be a particular way of cell death that was called "Type 2 death", as opposed to "Type 1 death" that referred to apoptosis. So we started a project in which we knocked down essential autophagy genes in cultured cell lines that were exposed to different lethal stressors including culture in nutrient-free conditions. We found that genetic or pharmacological inhibition of autophagy sensitized the cells to apoptotic death caused by the absence of nutrients (Boya et al. 2005 Mol Cell Biol PMID: 15657430). Based on these findings, we postulated that autophagy has a predominantly cytoprotective function and then generalized these findings in many different experimental settings, i.e., in different species (e.g., yeast, nematodes, flies, mice, human), cell types (e.g., primary cells and transformed, malignant cells), and in the context of different lethal stimuli (e.g., in the context of starvation, chemotherapy or radiotherapy). We also started to investigate the possible role of autophagy as a possible antiaging mechanism. This was spurred by the observation that genetic manipulations such as the knockout of tumor suppressor protein p53 (TP53) and pharmacological manipulations (such as the addition of resveratrol or spermidine to cultured cells) induced autophagy, as well as an increase in longevity in model organisms (such as nematodes in the case of the TP53 knockout, and yeast, nematodes and flies in the case of spermidine). We succeeded in abolishing this gain in lifespan by genetic inhibition of autophagy, demonstrating that the stimulation of autophagy has antiaging effects (Tasdemier et al. 2008 Nat Cell Biol PMID: 18454141; Tavernarakis et al. 2008 Autophagy PMID: 18728385; Eisenberg et al. 2009 Nat Cell Biol PMID: 19801973; Morselli et al. 2010, Cell Death Dis PMID: 21364612). Since then, we have continued this type of research, and we have published more than 100 additional papers documenting the antiaging effects of autophagy. Today we believe that any experimental manipulation that prolongs the health span and lifespan of model organisms, be it behavioral, nutritional, pharmacological or genetic, must induce autophagy to be efficient. For the sake of this discussion, it is important to note that nontoxic autophagy inducers that we refer to as "caloric restriction mimetics" have the capacity to improve cancer immunosurveillance. Hence, caloric restriction mimetics do not only prolong lifespan but also reduce the incidence of cancers.

Q2. ICD has been a transformative concept in oncology. What advancements in ICD research do you believe hold the greatest potential to revolutionize cancer treatment, and how close are we to integrating these into routine clinical practice?

Guido Kroemer: It is true that the idea of ICD that we coined 20 years ago (Casares et al. 2005 J Exp Med PMID: 16365148), has been a game changer in the conception of how cancers should be treated. Before we reported on the existence of ICD, it was commonly understood that anticancer agents, including chemotherapeutics, ionizing radiation and targeted agents such as tyrosine kinase inhibitors, would kill cancer cells by inducing apoptosis and that apoptotic cells would be unable to elicit immune response against dead-cell antigens or even be tolerogenic. We invalidated this dogma by showing that some specific anticancer agents exemplified by anthracyclines and oxaliplatin were able to induce a premortem stress response that then renders the subsequent cell death immunogenic. Part of this premortem stress response involves the induction of autophagy. We spent two decades of intense research to decipher the danger signals emanating from cells that undergo ICD as well as the molecular mechanisms that account for the exposure or release of such danger signals. We also studied the effects of these danger signals on innate immune cells, mostly dendritic cells.

Thanks to this work, we were able to build screening platforms that allow to identify drugs that are particularly potent ICD inducers, to engage in collaborative research projects with multiple pharmaceutical and biotech companies, and to identify and characterize novel ICD inducers. These efforts led to the FDA/EMA approval of several ICD inducers including small molecules (such as lurbinectedin for the treatment of small cell lung cancer) and several antibody drug conjugates in which the payloads are ICD inducers. The drug industry has well understood that ICD-inducing cytotoxicants are well superior to anticancer drugs that kill cancer cells in an immunologically silent fashion. In addition, multiple Phase 3 trials have shown that so-called induction chemotherapies with ICD-inducing agents sensitize to subsequent immune checkpoint blockade targeting CTLA-4, PD-1 or PD-L1, either in the adjuvant or in the neoadjuvant setting. In sum, the concept of ICD has already revolutionized oncological practice and has been integrated into the clinics. There is certainly more to come, but treatment with ICD inducers is already part of routine clinical practice.

Q3. Having contributed substantially to our understanding of cellular stress and death, what are your priorities for the next phase of your research, and what emerging technologies or methodologies excite you most about advancing this field?

Guido Kroemer: Our current work in the area of ICD focuses on three general ideas. First, we attempt to simplify the workflow for the identification of ICD-inducing agents based on AI-based structure-function predictions and automated microphotograph analyses (see for instance Cerrato et al. 2025 Mol Cancer PMID: 39702289). Second, we have elaborated a new technology involving initially immortal dendritic cell precursors that can be de-immortalized by molecular genetic tricks to screen for drugs that enhance the response to ICD at the level of these antigen presenting cells (see for example Zhao et al. Cancer Discov PMID: 37623817). Third, we are building a new screening platform called ONCO-PHENO-SCREEN, in which we will confront different cell types involved in the cancer-immunity dialogue (such as malignant cells, fibroblasts, dendritic cells and T cells) to build mini-immune systems allowing to identify a new generation of immuno-oncology (I-O) drugs.

However, these experimental systems are still based on a vision of the cancer-immunity dialogue that is centered on the tumor microenvironment. We are very much excited about the perspective to study this dialogue in the context of whole-body physiology, because we know that cancer immunosurveillance is profoundly influenced by systemic factors (Kroemer et al. 2023 Nat Med PMID: 36658422). Such systemic factors include neuroendocrine factors including the - mostly immunosuppressive - stress-associated immunomodulatory molecules (SAIMs) (Ma et al. 2025 Nat Rev Immunol PMID: 37833492) to which we recently added a new example, ACBP/DBI. Indeed, the neutralization of ACBP/DBI induces autophagy and improves cancer immunosurveillance in preclinical models. Moreover, ACBP/DBI levels increase in still apparently healthy individuals shortly before they are diagnosed with cancer (Montégut et al. 2024 Mol Cancer PMID: 39242519). In addition, we are very much interested in actionable mechanisms through which the gut microbiota affects anticancer immune responses in extra-intestinal tumors (Zitvogel et al. 2024 Immunity PMID: 39151425).

Q4. Over the years, you and your team have achieved remarkable breakthroughs in cancer cell biology. Could you share some of the most significant challenges you encountered during your research journey, and how you successfully overcame them?

Guido Kroemer: In contrast to my initial hopes and expectations, the world of research is highly conservative. The first reactions that a novel concept provokes are irritation and disbelief. I have encountered major difficulties in rendering acceptable several of our breakthrough concepts including the ideas that (i) apoptosis involves the cessation of mitochondrial functions  and hence cannot be avoided by caspase inhibition; (ii) autophagy is a primordially cytoprotective and antiaging mechanisms; (iii) apoptotic cell death can be immunogenic depending on the constellation of premortem stress signals; and (iv) systemic stress signals emanating from the gut or neuroendocrine circuitries profoundly affect the cancer-immunity dialogue. Fortunately, we were able to work on each of these concepts for protracted periods until they were confirmed by our colleagues, including those working in pharmacological and clinical development. Right now, we are confronted with the problem that our team is the only one in the world to study ACBP/DBI as a drug target. The general perception is the following: If they are the only ones to work on this topic, they must be wrong. For this reason, we will continue to work on ACBP/DBI with unwavering obstinacy. Simultaneously, I invite my colleagues to follow our footsteps and offer them to use our reagents.

Q5. What advice would you offer to medical students and researchers aspiring to specialize in cancer biology? How can they make meaningful contributions to the field and build a career as impactful as yours?

Guido Kroemer: I think it is extremely important to be able to think out of the box and to invent radically new scientific questions that can be answered by suitable up-to-date methodologies, preferentially using a broadly orthogonal approach. So you need to develop a broad intellectual and technological culture and then spend uncountable hours to develop and execute your experimental plan. Once you are absolutely sure about the novel concept that you develop, you are ready to defend it in front of the public and to attempt to publish it. But be prepared to earn irritation and disbelief rather than admiration and adhesion. Be stubborn and resilient, because it will take many years, usually a decade a longer, to collect the fruits of your incursion into terra incognita. Be prepared to be a lone traveler, but look out for allies that resemble you. The future is bright.

We would like to express our sincere gratitude to Professor Kroemer for sharing his valuable insights and inspiring journey with us. His groundbreaking research continues to drive innovation in aging and cancer immunotherapy, and we are honored to feature him in this inaugural interview.

Respectfully Submitted by the Editorial Office of ACRT.