Crosstalks between inflammasome and autophagy in cancer

Abstract

Both inflammasomes and autophagy have important roles in the intracellular homeostasis, inflammation, and pathology; the dysregulation of these processes is often associated with the pathogenesis of numerous cancers. In addition, they can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses, including cancer. Multiple molecular mechanisms connect the autophagy pathway to inflammasome activation and, through this, may influence the outcome of pro-tumor or anti-tumor responses depending on the cancer types, microenvironment, and the disease stage. In this review, we highlight the rapidly growing literature on the various mechanisms by which autophagy interacts with the inflammasome pathway, to encourage additional applications in the context of tumors. In addition, we provide insight into the mechanisms by which pathogen modulates the autophagy-inflammasome pathway to favor the infection-induced carcinogenesis. We also explore the challenges and opportunities of using multiple small molecules/agents to target the autophagy/inflammasome axis and their effects upon cancer treatment. Finally, we discuss the emerging clinical efforts assessing the potential usefulness of targeting approaches for either autophagy or inflammasome as anti-cancer strategies, although it remains underexplored in terms of their crosstalks.

Keywords: Autophagy; Cancer; Inflammasome; Mitochondrial ROS; Mitophagy.

Fig. 1

Overview of macroautophagy and mitophagy. Autophagy has dual roles in cancer, depending on the disease stage and tumor microenvironment. A summary of macroautophagy (autophagy) and mitophagy is shown. Autophagy can be divided into three steps: initiation, elongation, and maturation. In each step, several key players participate in the formation of phagophore (initiation), autophagosome elongation, and maturation (fusion of autophagosomes and lysosomes). In mitophagy, dysfunctional mitochondria are recognized by Parkin-dependent or Parkin-independent pathways. Ubiquitin, ubiquitin-binding proteins, and autophagy receptors, such as p62, NBR1, NDP52, and OPTN, are involved in the Parkin/PINK1-dependent mitophagy activation. In the Parkin-independent mitophagy pathway, several mitophagy receptors (Nix/BNIP3L, BNIP3, FUNDC1, BCL2L13, and FKBP8) direct damaged mitochondria to the LC3-mediated autophagy machinery

Fig. 2

NLRP3 and AIM2 inflammasome pathways. The NLRP3 inflammasome activation is mediated through two signals: Toll-like receptor (TLR)/tumor necrosis factor receptor (TNFR)-mediated NF-κB pathway activation or inflammasome complex assembly (NLRP3, ASC, and pro-caspase-1) triggered by particulate matter (lysosomal destabilization or cathepsin B release), mitochondrial ROS generation, intracellular calcium influx, or potassium efflux. The activated NLRP3 inflammasome promotes IL-1β and IL-18 maturation and induces pyroptotic cell death (osmotic lysis of cells). AIM2 inflammasome assembly is induced by the recognition of cytosolic DNA and leads to pyroptosis and IL-1β/IL-18 maturation

Fig. 3

Crosstalk between autophagy and inflammasome activation in cancer. The crosstalk between autophagy and inflammasome activation regulates multiple physiological and pathological responses, including cancer. Mitochondrial dysfunction and mitochondrial ROS generation can activate autophagy/mitophagy, as well as act as the second signal for inflammasome activation and pyroptosis. Dysfunctional autophagy results in excessive mitochondrial oxidative stress, leading to autophagic cell death, inflammasome activation, and pyroptosis. Elevated mitochondrial ROS levels can also promote oncogenesis, chemoresistance, and metastasis. Furthermore, mitochondria-associated membranes at the ER-mitochondria contact sites are signaling hubs for mitochondrial Ca²⁺ transfer from the ER to mitochondria through IP3R3s, mediating NLRP3 inflammasome activation in response to mitochondrial damage. IP3R3s are upregulated in various cancers

Fig. 4

The role of mitochondrial ROS in the regulation of the autophagy/inflammasome axis at MAMs in non-malignant cells, cancer cells, and chemosensitized cells. MAMs are signaling hubs, playing crucial roles in the crosstalk between autophagy and inflammasome activation, as well as intracellular Ca²⁺ signaling, mitochondrial lipid metabolism, and bioenergetics. Mitochondrial dysfunction and subsequent mitochondrial ROS generation activate autophagy/mitophagy, which negatively regulates NLRP3 inflammasome activation in non-malignant cells. Cancer cells are characterized by elevated mitochondrial ROS levels, accompanied by the upregulation of antioxidant machinery components. The role of mitochondrial ROS in the crosstalk between autophagy and inflammasome activation in cancer cells remains unclear. In chemosensitized cells, excessive production of mitochondrial ROS results in autophagic and pyroptotic cell death. Although the role of IP3R in the regulation of the autophagy/inflammasome axis remains unknown, IP3R inhibition can suppress tumor growth