Inflammation and tumor progression: signaling pathways and targeted intervention

Abstract

Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates tumor progression and treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation of dendritic cells (DCs) and antigen presentation, leading to anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers and activators of transcription (JAK-STAT), toll-like receptor (TLR) pathways, cGAS/STING, and mitogen-activated protein kinase (MAPK); inflammatory factors, including cytokines (e.g., interleukin (IL), interferon (IFN), and tumor necrosis factor (TNF)-α), chemokines (e.g., C-C motif chemokine ligands (CCLs) and C-X-C motif chemokine ligands (CXCLs)), growth factors (e.g., vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β), and inflammasome; as well as inflammatory metabolites including prostaglandins, leukotrienes, thromboxane, and specialized proresolving mediators (SPM), have been identified as pivotal regulators of the initiation and resolution of inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, and SPM have been developed to specifically modulate inflammation in cancer therapy, with some of these factors already undergoing clinical trials. Herein, we discuss the initiation and resolution of inflammation, the crosstalk between tumor development and inflammatory processes. We also highlight potential targets for harnessing inflammation in the treatment of cancer.

Fig. 1

SPM biosynthesis and their roles in the resolution of inflammation. a SPM including lipoxins, E-series resolvins, D-series resolvins, protectins (neuroprotectin D1), and maresins are biosynthesized from arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The main structures of these SPM and their receptors are depicted. b Anti-inflammatory lipid mediators (LM) class are produced to help restore tissue homeostasis during the resolution of inflammation

Fig. 2

Inflammatory signaling pathways involved in cancer development. Intracellular signaling pathways involved in inflammation and tumor development are activated via distinct receptors at the cell membrane. Subsequent downstream signaling events activate several well-characterized pathways: NF-κB, MAPK, JAK-STAT, and PI3K-AKT. These pathways regulate various inflammatory factors

Fig. 3

The relationship between inflammation and cancer development. During acute inflammatory responses (left panel): after tumor antigen uptake or activation by TLR agonist, mature DCs can regulate anti-tumor immune responses by inducing inflammatory responses via multiple mechanisms, such as cross-presenting the tumor antigens and priming tumor-specific CD8⁺ T cells, polarizing immune cells toward tumor suppression (e.g., M1 polarization of TAMs), recruiting NK cells which can sustain T-cell responses. However, if the acute inflammatory reaction does not resolve in time, it subsequently transforms into chronic inflammation (right panel). In this microenvironment, cancer cells can not only hijack DCs to prevent TAA presentation, but also recruit a large number of immunosuppressive cells (e.g., MDSCs, Treg cells, Breg cells, M2-TAMs, N2-TANs, and Th2 cells) by secreting various cytokines, chemokines, and inflammatory mediators. In turn, these immunosuppressive cells provide a rich proangiogenic and pro-tumoral microenvironment, and prevent the innate immunity and T-cell anti-tumor immunity

Fig. 4

Harnessing the inflammation in cancer therapy. Several promising strategies for regulation of cancer-related inflammation have been suggested to improve anti-tumor response. On the one hand, inducing inflammation and modulating immune cell activation would overcome T-cell exclusion, turning “cold” tumors into “hot” tumors, for instance, local inflammation induced by irradiation or oncolytic viruses can promote innate immunity by activating nucleic-acid-sensing cytosolic receptors (cGAS–STING or RLRs) and subsequent type I IFN response. Besides, promoting DC maturation by cGAS–STING, TLR agonist, DC vaccine, or injection of GM-CSF can induce an acute inflammatory response and priming of T lymphocytes, which facilitate tumor regression. On the other hand, inhibiting chronic inflammation by anti-inflammatory drugs (e.g., aspirin) or accelerating inflammation resolution by proresolving mediators (SPM, e.g., lipoxins, resolvins, protectins, and maresins) also display an overall survival benefit for anti-cancer therapy. Furthermore, limitations of the infiltration and function of immunosuppressive cells (e.g., MDSCs, Treg cells, Breg cells, and M2-TAMs) by blocking inflammatory pathways is another way to restore immune surveillance and promote anti-tumor immunity. Green represents factors that enhancing these cancer-inhibiting inflammation, while red represents factors that blocking these cancer-promoting inflammation, would be beneficial to improve the effect of anti-tumor therapy