Lorenzo Galluzzi

Ferroptosis is a variant of regulated cell death (RCD) elicited by an imbalance of cellular redox homeostasis that culminates with extensive lipid peroxidation and rapid plasma membrane breakdown. Since other necrotic forms of RCD, such as necroptosis, are highly immunogenic, ferroptosis inducers have attracted considerable attention as potential tools to selectively kill malignant cells while eliciting therapeutically relevant tumor-targeting immune responses. However, rather than being consistently immunogenic, ferroptosis mediates context-dependent effects on anticancer immunity. The inability of ferroptotic cancer cells to elicit adaptive immune responses may arise from contextual deficiencies in intrinsic aspects of the process, such as adjuvanticity and antigenicity, or from microenvironmental defects imposed by ferroptotic cancer cells themselves or elicited by the induction of ferroptosis in immune cells.

Serine is critical for supporting cancer metabolism, and as such, depriving malignant cells of this non-essential amino acid exerts anticancer effects, in large part, through disrupting their metabolic pathways. However, the impact of these metabolic defects on tumor-targeting immunity remains poorly understood. Here, we show that restricting endogenous and exogenous serine in colorectal cancer (CRC) cells results in mitochondrial dysfunction coupled to cytosolic mitochondrial DNA accumulation and cGAS/STING1-dependent type I interferon secretion. Serine-deprived tumors have suppressed growth, accompanied by type I interferon signaling and tumor infiltration by immune effector cells. Blocking cGAS/STING1 signaling in tumor cells limits the immunostimulatory and anticancer effects of serine deprivation. Moreover, serine-depleted tumors exhibit increased sensitivity to a programmed cell death 1 blocker …

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.

Chromosomal instability (CIN) contributes to tumor initiation, progression, and metastatic dissemination. In a recent issue of Nature, Li et al. characterized a cancer cell-heterologous mechanism through which CIN drives metastasis upon the rewiring of cGAS-STING1 signaling in cancer cells and the consequent establishment of local immunosuppression.Chromosomal instability (CIN) accelerates the pace at which cancer cells acquire genomic alterations that foster oncogenesis. 1 CIN is indeed poorly tolerated in normal cells, but characterizes most human tumors, at least in part as moderate degrees of CIN provide developing neoplasms with a broad genomic substrate for accelerated evolution despite the existence of numerous cellintrinsic and microenvironmental (including immunological) oncosuppressive mechanisms. 2 That said, excessive CIN levels also limit tumor progression, largely reflecting the …

Mammalian cells react to the accumulation of double-stranded (ds)DNA in the cytosol by secreting antiviral and proinflammatory cytokines, notably type I interferon (IFN). Recent data reported by Tani et al. demonstrate that overactivation of this pathway is prevented by an adaptive feedback mechanism elicited by type I IFN receptors and executed by the exonuclease three prime repair exonuclease 1 (TREX1).

LTX-315 is a synthetic cationic oncolytic peptide with potent anticancer activity but limited toxicity for non-malignant cells. LTX-315 induces both immunogenic tumor cell death and generation of tumor-specific immune responses in multiple experimental tumor models. Given the central role of dendritic cell (DC) maturation in the induction of antigen-specific immunity, we investigated the effect of LTX-315 treatment on the maturation of tumor-infiltrating DCs (TiDCs) and the generation of anti-melanoma immunity. We found that LTX-315 treatment induces the maturation of DCs, both indirectly through the release of cancer cell-derived damage-associated molecular patterns (DAMPs)/alarmins and nucleic acids (DNA and RNA) capable of triggering distinct Toll-like receptor (TLR) signaling, and, directly by activating TLR7. The latter results in the ignition of multiple intracellular signaling pathways that promotes DC maturation, including NF-κB, mitogen activated protein kinases (MAPKs), and inflammasome signaling, as well as increased type 1 interferon production. Critically, the effects of LTX-315 on DCs the consequent promotion of anti-melanoma immunity depend on the cytosolic signal transducer myeloid differentiation response gene 88 (MyD88). These results cast light on the mechanisms by which LTX-315 induces DC maturation and hence elicits anticancer immunity, with important implications for the use of LTX-315 as an anticancer immunotherapeutic.

Immunogenic cell death (ICD), which results from insufficient cellular adaptation to specific stressors, occupies a central position in the development of novel anticancer treatments. Several therapeutic strategies to elicit ICD — either as standalone approaches or as means to convert immunologically cold tumours that are insensitive to immunotherapy into hot and immunotherapy-sensitive lesions — are being actively pursued. However, the development of ICD-inducing treatments is hindered by various obstacles. Some of these relate to the intrinsic complexity of cancer cell biology, whereas others arise from the use of conventional therapeutic strategies that were developed according to immune-agnostic principles. Moreover, current discovery platforms for the development of novel ICD inducers suffer from limitations that must be addressed to improve bench-to-bedside translational efforts. An improved …

Cancer cells undergoing immunogenic cell death (ICD) can initiate adaptive immune responses against dead cell‐associated antigens, provided that (1) said antigens are not perfectly covered by central tolerance (antigenicity), (2) cell death occurs along with the emission of immunostimulatory cytokines and damage‐associated molecular patterns (DAMPs) that actively engage immune effector mechanisms (adjuvanticity), and (3) the microenvironment of dying cells is permissive for the initiation of adaptive immunity. Finally, ICD‐driven immune responses can only operate and exert cytotoxic effector functions if the microenvironment of target cancer cells enables immune cell infiltration and activity. Multiple forms of radiation, including non‐ionizing (ultraviolet) and ionizing radiation, elicit bona fide ICD as they increase both the antigenicity and adjuvanticity of dying cancer cells. Here, we review the molecular …