Ferroptosis, necroptosis, and pyroptosis in anticancer immunity

Abstract

In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved considerable success in the clinic. However, ICIs are significantly limited by the fact that only one third of patients with most types of cancer respond to these agents. The induction of cell death mechanisms other than apoptosis has gradually emerged as a new cancer treatment strategy because most tumors harbor innate resistance to apoptosis. However, to date, the possibility of combining these two modalities has not been discussed systematically. Recently, a few studies revealed crosstalk between distinct cell death mechanisms and antitumor immunity. The induction of pyroptosis, ferroptosis, and necroptosis combined with ICIs showed synergistically enhanced antitumor activity, even in ICI-resistant tumors. Immunotherapy-activated CD8+ T cells are traditionally believed to induce tumor cell death via the following two main pathways: (i) perforin-granzyme and (ii) Fas-FasL. However, recent studies identified a new mechanism by which CD8+ T cells suppress tumor growth by inducing ferroptosis and pyroptosis, which provoked a review of the relationship between tumor cell death mechanisms and immune system activation. Hence, in this review, we summarize knowledge of the reciprocal interaction between antitumor immunity and distinct cell death mechanisms, particularly necroptosis, ferroptosis, and pyroptosis, which are the three potentially novel mechanisms of immunogenic cell death. Because most evidence is derived from studies using animal and cell models, we also reviewed related bioinformatics data available for human tissues in public databases, which partially confirmed the presence of interactions between tumor cell death and the activation of antitumor immunity.

Natural Products as Inducers of Non-Canonical Cell Death: A Weapon against Cancer

“…The most effective drugs currently used in the oncological field are, among others, the vinca alkaloids vincristine and vinblastine, etoposide, paclitaxel, topotecan, and irinotecan, which all originate from terrestrial plants [ 9 ]. Interestingly, although until a few years ago apoptosis was the anticancer mechanism of action described for these compounds, it has been shown that some of them also induce non-canonical cell deaths [ 10 , 11 ]. Many other different natural compounds were thus explored and identified as promoters of non-canonical cell death.…”

Regulated Necrotic Cell Death in Alternative Tumor Therapeutic Strategies

“…Necroptosis, pyroptosis, and ferroptosis are discussed in this review. These types of cell death are caused by membrane disruption induced by specific signal cascades [ 136 ], which can elicit an inflammatory response within the tumor tissue [ 137 ]. The induction of RNCD in tumor tissues does not necessarily lead to positive results in cancer patients, since the inflammatory response in the tissues can have favorable or adverse effect depending on the tumor type [ 138 ].…”

A Ferroptosis-associated Gene Signature for the Prediction of Prognosis and Therapeutic Response in Luminal-type Breast Carcinoma

“…In recent years, cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has achieved great success in basic medical research and clinical practice. However, ICIs are signi cantly limited by the fact that only one-third of patients with most types of cancer respond to these agents [43]. Tumor cells undergoing ferroptosis can trigger robust antitumor immunity in vivo and in vitro, and their e cacy can be synergistically improved by ICIs, even in ICI resistance.…”