Microbiome-driven anticancer therapy: A step forward from natural products

Abstract

Human microbiomes, considered as a new emerging and enabling cancer hallmark, are increasingly recognized as critical effectors in cancer development and progression. Manipulation of microbiome revitalizing anticancer therapy from natural products shows promise toward improving cancer outcomes. Herein, we summarize our current understanding of the human microbiome-driven molecular mechanisms impacting cancer progression and anticancer therapy. We highlight the potential translational and clinical implications of natural products for cancer prevention and treatment by developing targeted therapeutic strategies as adjuvants for chemotherapy and immunotherapy against tumorigenesis. The challenges and opportunities for future investigations using modulation of the microbiome for cancer treatment are further discussed in this review.

Keywords: anticancer; cancer; chemotherapy; immunotherapy; microbiota.

Figure 1

Interplay between microbiota and cancer through multiple mechanisms. The molecular mechanisms between microorganisms and tumors include direct DNA‐damaging effects of bacterial toxins and epigenetic regulation, inflammatory responses driven by signaling pathways following infection, and influence on antitumor immune responses. The microbiome plays an ambivalent role in antitumor immunity. (1) Microbial antigens could be presented by tumor cells, activating anti‐tumor immune responses. (2) The microbes stimulate inflammatory TIME by antigens and metabolites. (3) The microbes induce the differentiation of TAMs and recruit MDSCs, forming an immunosuppressive TME. (4) The microbes interact with inhibitory immune checkpoints, suppressing immune cells. BFT, Bacteroides fragilysin; DC, dendritic cell, ETBF, enterotoxigenic Bacteroides fragilis; MDSC, myeloid‐derived suppressor cell; ROS, reactive oxygen species; TAM, tumor‐associated macrophage; TIME, tumor's immune microenvironment; TLR‐4, Toll‐like receptor 4.

Figure 2

Combination of natural products and therapeutic drugs against cancer by targeting microbiota. (A) The microbiota and microbial metabolites can modulate chemotherapy efficacy. Natural products for enhancing chemosensitivity via microbiota are likely to be found. (B) Fusobacterium nucleatum has been found to contribute to chemoresistance. There is a possibility that Morus alba, maslinic acid, and oleanolic acid might overcome chemoresistance by targeting F. nucleatum. (C) The chemotherapeutic toxicities of irinotecan (CPT‐11) could be alleviated using an Escherichia coli β‐glucuronidase inhibitor that includes baicalein, scutellarin, and luteolin. Moreover, natural compounds including ABPs, CMP, and diadzein alleviate 5‐FU‐related toxicity by altering microbial diversity. (D) The immunotherapy efficacy could be enhanced by supplying microbial metabolites, such as VPA and polysaccharides. (E) Natural products regulating microbiota diversity contribute toward optimizing ICI responses. (F) Both specific baseline and dysbiosis are associated with irAEs. More studies are warranted to investigate which and how natural products modulate microbiota to induce immunotherapeutic toxicity. 5‐FU, 5‐Fluorouracil; ABPs, Albuca bracteate polysaccharides; CMP, carboxymethyl pachyman; CPT, camptothecin; CTX, cyclophosphamide; FUDR, floxuridine; ICI, immune checkpoint inhibitor irAEs, immune‐related adverse events; SCFA, short‐chain fatty acid; SN38G, SN‐38 glucuronide; TLR‐4, Toll‐like receptor 4; VPA, valproic acid.