Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication

Abstract

In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.

Keywords: Clinical implication; Cytokine; Mechanism; Pyroptosis; Tumor microenvironment.

Fig. 1

Summary of the mechanism of pyroptosis. In caspase-1-dependent pathway, the inflammasome sensors triggered by DAMPs and/or PAMPs could activate caspase-1. Subsequently, a cascade of events like the cleavage of GSDMD, maturation of pro-IL-1β and pro-IL-18, release of pro-inflammation cytokines, formation of GSDMD pores and ultimately cell membrane rupture. In caspase-4/5/11-dependent pathway, inflammasome sensors can be directly activated by LPS, which is also a GSDMD-dependent pyroptotic pathway. In other pathways, caspase-3 triggers pyroptosis via GSDME while caspase-8 initiates pyroptosis via GSDMC. Additionally, pyroptosis can be activated without caspase family. CD8 + T cells and NK cells can secrete granzyme A and cause pyroptosis mediated by GSDMB, while release of granzyme B could induce pyroptosis via GSDME

Fig. 2

The inducing factors of pyroptosis in tumor microenvironment. Inflammasome activation, pro-inflammatory cytokines, hypoxia, and drug therapies can initiate pyroptosis in the TME. PRRs identify PAMPs or DAMPs and further trigger the formation of inflammasomes within the TME. Eventually, pro-inflammatory cytokines release and pyroptosis occurs. Hypoxia in TME promotes the GSDMC-dependent pyroptosis with PD-L1 and phosphorylated Stat3. Diverse drug therapies can induce pyroptosis in multi-forms. Pro-inflammatory cytokines secreted by immune cells and released by pyroptotic tumor cells may cause peripheral inflammation, which may further recruit and activate more immune cells. Additionally, immune cells may directly kill tumor cells, thus enhancing the peripheral inflammation

Fig. 3

Dual role of pyroptosis in tumor microenvironment remodeling and metastasis. Pyroptosis plays dual roles in TME. The anti-tumor effects could be concluded in two ways, the direct killing effect on tumor cells and immune cell activation. Membrane lysis by gasdermins and disruption of cellular homeostasis are two primary mechanisms through which pyroptosis mediates the killing of tumor cells. While dying cells may release pro-inflammation cytokines and DAMPs which may further attract and recruit immune cells. The pro-tumor effects of pyroptosis can be multifactorial. Peripheral inflammation caused by pyroptosis facilitates the tumor progression. Additionally, NLRP3 inflammasome-mediated pyroptosis can promote angiogenesis in tumors. The impact of pyroptosis on tumor metastasis is complex and context-dependent, and may enhance tumor infiltration and metastasis via IL-1 and IL-18 cytokine release

Fig. 4

Cytokines in tumor microenvironment participate in both immune response and tumor progression

Fig. 5

The crosstalk between pyroptosis and cytokines in cGAS-STING pathway. The cGAS-STING pathway (in purple arrow) is the primary sensor for cellular cytosolic dsDNA, enabling the innate immune system to respond to diverse pathogens and dying cells. Cytosolic DNA sensor cGAS binds dsDNA to form cGAS-dsDNA complex, and subsequently activates cGAMP. This initiates a series of downstream effects including STING activation, recruitment of TBK1, and phosphorylation of IRF3. Ultimately, innate immune response and diverse cytokines release. Pyroptosis can regulate cGAS-STING pathway via different components and cytokines (in blue arrow). Additionally, the cGAS-STING pathway can also promote pyroptosis mainly through NLPR3 and AIM2 inflammasomes (in red arrow). The crosstalk between pyroptosis and cytokines in cGAS-STING pathway together forms a complex network

Fig. 6

Summary of the therapeutic targets in TME

Fig. 7

Emerging research and technologies in TME. High-throughput cytokine assays provide a comprehensive view of cytokine profiles in the TME by quantifying multiple cytokines simultaneously. Single-cell sequencing allows for studying the co-evolution of tumor cells and TME components by profiling small quantities of cells. Spatial transcriptomics identifies cell types and their functional states within the TME by profiling thousands of genes across spatially defined tissue regions concurrently