Targeting inflammation as cancer therapy

Abstract

Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies.

Keywords: Cancer; Inflammation; Therapy.

Fig. 1

A schematic of the crosstalk between major inflammatory cells and inflammatory molecules in the tumor microenvironment. The major inflammatory cells include T helper (Th1) cell, regulatory T cells (Tregs), cytotoxic CD8 + T cells, macrophages, neutrophils, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and dendritic cells (DCs). Figures created with BioRender. Abbreviations: CXCR, CXC-chemokine receptor; CXCL, chemokine (C-X-C motif) ligand; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon

Fig. 2

Overview of the cyclooxygenase pathway and the action mechanisms of cyclooxygenase-targeting strategies in cancer. The COX-2/PGE2 pathway facilitates the maintenance of immunosuppressive TME by activating a wide range of immunosuppressive immune cells. Inhibitors of COX-2 signaling such as NSAIDs are potentially a good combination partner for immunotherapies. Figures created with BioRender. Abbreviations: PGH2, prostaglandin H2; PGG2, prostaglandin G2; PLA2, PLC, PLD, phospholipases A2, C, and D; PGE2, prostaglandin (PG) E2; PGI2, prostacyclin; PGD2, prostaglandin D2; PGF2α, prostaglandin F2α; TXA2, thromboxane A2; MDSC, myeloid-derived suppressor cells

Fig. 3

Molecular mechanisms that mediate the effects of inflammation-targeting strategies in cancer. These inflammation-targeting strategies inhibit the COX, JAK/STAT, and TGF-β signaling which support cancer cell survival, proliferation, and invasion. Figures created with BioRender. NSAIDs, non-steroidal anti-inflammatory drugs; COX, cyclooxygenase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa B; CXCR, CXC-chemokine receptor; CXCL, chemokine (C-X-C motif) ligand; TGF-β, transforming growth factor-β; TGF-βR, TGF-β receptor; IL, interleukin; IFN, interferon; STAT3, signal transducer and activator of transcription 3; SMAD, mothers against decapentaplegic