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Galluzzi and Kroemer take advantage of a large study of somatic copy number alterations to revisit the previously suggested idea that cancer aneuploidy frequently arises from genome duplication.

Petroni et al. report that the infiltration of IL-17A-secreting γδ T cells in the tumor microenvironment coupled with the accumulation of immunosuppressive macrophages is associated with resistance to CDK4/CDK6 inhibition in HR⁺HER2⁻ breast cancer.

Kroemer and colleagues discuss evidence supporting the importance of immunosurveillance in natural and therapy-induced killing of breast tumors.

Recent studies in mouse models of viral infection showed that precursors of terminally exhausted T cells emerge early during the course of disease. Here, Galluzzi discusses these findings and what they may mean for our understanding of tumour immunology and responses to immunotherapy with immune checkpoint blockade.

Autophagy controls cellular homeostasis and influences immune responses. Galluzzi and colleagues show that tumor cell autophagy opposes inflammatory cell death following radiation therapy and can be inhibited to enhance antitumor responses.

Autophagy is fundamental to cellular homeostasis and also has a central role in the development and progression of cancer. However, autophagy is also required for optimal immune system function, including the development of an anticancer immune response. In this Perspective, the authors present the available preclinical and clinical evidence that autophagy might enhance the effectiveness of both immunogenic chemotherapy and radiotherapy, as opposed to the general view of inhibition of autophagy as an antitumour strategy.

Mitochondrial integrity controls cellular and immunological homeostasis in various pathophysiological settings. Recent findings suggest that VDAC2 antagonizes the ability of IFNγ to drive mitochondrial permeabilization in malignant cells by inhibiting BAK, thus promoting cell survival and immunoevasion.

Dysregulated autophagy is associated with a variety of conditions, including cancer, neurodegenerative diseases, cardiovascular disorders and infectious diseases. However, despite significant efforts, no specific modulators of autophagy have yet been moved into the clinic. Here, Galluzziet al. discuss the therapeutic potential of autophagy modulators and consider the key challenges that have limited their development.

Lorenzo Galluzzi and colleagues discuss the molecular mechanisms through which mitochondrial dysfunction elicits inflammatory reactions, the cellular pathways that are in place to control them and how the dysregulation of these systems contributes to pathology.

The improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have developed strategies for eliminating mitosis-incompetent cells, one of which is mitotic catastrophe. From a functional perspective, mitotic catastrophe can be defined as an oncosuppressive mechanism that precedes (and is distinct from) apoptosis, necrosis or senescence.

During the past few decades, the vital and lethal functions of mitochondria have been investigated extensively. Data now demonstrate that these organelles also regulate the innate immune response by modulating inflammasome-mediated generation of proinflammatory cytokines.

Current preclinical models to investigate human HR + breast cancer progression and response to immunotherapy in vivo are limited. Here, the authors demonstrate that mammary tumours driven by a synthetic progestin combined with an oral carcinogen recapitulate several immunobiological features of human HR + breast cancers.

Mammalian caspases are a group of cysteine proteases historically categorized into an ‘inflammatory’ subgroup and an ‘apoptotic’ subgroup, although accumulating evidence indicates that this distinction is not as clearcut as initially thought. Here, we discuss the functions of inflammatory caspases and apoptotic caspases, while proposing that all caspases ultimately regulate inflammation, either directly or by controlling cell death.

Radiotherapy has an established role in the treatment of many patients with cancer, with evidence suggesting that this modality can also have immunostimulatory effects in certain scenarios. More recently, evidence has emerged supporting a role of the microbiome in influencing the incidence and severity of toxicities in patients receiving radiotherapy as well as in mediating possible synergy with other therapeutic interventions, including immunotherapy. In this Review, the authors explore the clinical potential of these emerging relationships.

Voltage-dependent anion channels (VDACs) are thought to participate in mitochondrial-membrane permeabilization, an event that frequently delimits the frontier between cell life and death. Recent work casts doubts on their contribution to mitochondrial cell death.

Immune checkpoint inhibitors (ICIs) have dramatically improved the treatment of many tumours, but only a subset of patients respond when ICIs are used as standalone immunotherapeutic interventions. Here, Galluzzi and colleagues discuss the potential of harnessing clinical agents that target oncogene and non-oncogene addiction to enhance ICI sensitivity by converting immunologically ‘cold’ tumours into ‘hot’ lesions.

Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.

A crucial role of the immune system in cancer progression and response to therapy has recently emerged. Here, Galluzzi and colleagues discuss the immune parameters that may predict the therapeutic response of patients to chemotherapeutics, and review the mechanisms by which current antineoplastic agents activate the immune system against cancer.

Radiotherapy has several key attributes that make it an attractive combination partner for immunotherapy; however, numerous clinical trials investigating the combination of these two treatment modalities have failed to demonstrate clear improvements in patient outcomes. In this Review, Galluzzi and colleagues discuss the evidence indicating that radiotherapy administered according to standard schedules and target volumes might impair immune fitness and, therefore, propose that adaptation of the radiotherapy regimens to immunotherapy (and not vice versa) might synergistically enhance the antitumour immune response to achieve meaningful clinical benefits.

Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.

Dysregulated cell death occurs in many human diseases, and modulating the associated pathways has proved effective in the treatment of cancer, stroke and neurodegenerative disorders. In their review, Kepp and colleagues provide an overview of assays capable of accurately quantifying distinct cell death pathways, focusing on those techniques that are applicable to high-throughput screening.

Cellular metabolism is substantially altered during oncogenesis and tumour progression, and targeting these metabolic changes is being actively pursued in the development of selective antineoplastic agents. Here, Kroemer and colleagues discuss the intimate relationship between metabolism and malignancy, focusing on therapeutic strategies and emerging agents targeting the metabolic rearrangements of cancer cells.

Type I interferons (IFNs) are best known for their role in antiviral immunity. As discussed in this Review, recent evidence indicates that these cytokines also have an integral role in natural and therapy-induced anticancer immunity. Harnessing the antineoplastic properties of type I IFNs may lead to the development of ever-more effective anticancer therapies.

Whether autophagy — an intracellular degradation pathway — contributes to or protects against damage following different types of acute brain injury is unclear. Here, Kroemer and colleagues review investigations into the effects of autophagy in excitotoxicity, acute exposure to neurotoxins, neonatal asphyxia, stroke and neurotrauma.

Mitochondrial dysfunction has a major role in the pathogenesis of multiple cardiovascular disorders. In this Review, Galluzzi and colleagues discuss the therapeutic potential of mitochondria-targeting agents in the treatment of cardiovascular disease, examine the obstacles that have limited their development thus far, and identify strategies for the development of these promising therapeutic tools.

Radiation therapy has for decades been a standard form of treatment for many cancers. A Review by Galluzzi and colleagues explores the effects of radiation therapy in the context of the immune response.

Autophagy and cancer: In this Review, Galluzzi and colleagues discuss the cellular and molecular mechanisms whereby autophagy functions in multiple aspects of malignant disease, including cancer initiation, progression and responses to therapy.

Radiotherapy has attracted considerable attention as a means to alter the immune cell compartment of breast malignancies in support of increased sensitivity to immunotherapy. Recent data from Schalck and colleagues corroborate the notion that dose is a critical determinant of the immunological effects of radiotherapy on the tumor microenvironment.

Cellular and organismal aging have been consistently associated with mitochondrial dysfunction and inflammation. Accumulating evidence indicates that aging-related inflammatory responses are mechanistically linked to compromised mitochondrial integrity coupled with mtDNA-driven CGAS activation, a process that is tonically inhibited by mitophagy.

The net effect of type I interferon (IFN-I) signaling on tumor control depends on various factors, including the potential engagement of adaptive anticancer immunity. New findings delineate a targetable epigenetic mechanism by which suboptimal IFN-I signaling promotes tumor progression in the context of cancer stem cell expansion and immunoevasion.

The key roles of mitochondria in energy production and the regulation of apoptosis are frequently deregulated in cancer. Attempts to activate the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization, could represent a promising strategy for the treatment of cancer.

Beyond exhaustion, CD8⁺ T cells can adopt various dysfunctional states, including tolerant, anergic, senescent, ignorant and dying states, that compromise their ability to eradicate viruses or tumours. Here, the authors describe how these states may be distinguished, how they arise and the implications for immunotherapy.

Cellular stress responses primarily serve to rectify stress-associated damage. However, these responses are also coupled with the generation of various signals that are transmitted to the cellular microenvironments or even across tissues. This communication generally supports the maintenance of systemic homeostasis but can also result in pathology.

Immunogenic cell death (ICD) is central to both homeostatic and pathophysiological events. Kroemer et al. review the mechanisms of ICD and its role in therapy and disease.

Although necrosis was regarded as an uncontrolled mode of cell death, evidence now shows that it can be highly regulated. The initiation of programmed necrosis (necroptosis) by death receptors requires receptor-interacting protein 1 (RIP1) and RIP3, and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes.

Here, the authors introduce the idea that a spectrum of metabolic states of immune cells can provide a basis for categorizing human diseases. They explore the metabolic and interlinked signalling requirements of T cells responding to acute infection and how metabolic reprogramming of T cells is linked to disease.

In addition to regulating the cascades leading to cell death, mitochondria detect cell stress signals (for example, viral infection) and themselves emit danger signals in response to perturbations of homeostasis to trigger cell-intrinsic or systemic responses. They can therefore be considered as master regulators of danger signalling.

Initiation of an adaptive immune response depends on the detection of both antigenic epitopes and adjuvant signals. Infectious pathogens and cancer cells often avoid immune detection by limiting the release of danger signals from dying cells. When is cell death immunogenic and what are the pathophysiological implications of this process?

Kroemer and colleagues discuss the converging signalling mechanisms that lead to mitochondrial membrane permeabilization and trigger neuron death after severe brain injury. They also highlight how knowledge of these mechanisms might be exploited therapeutically.