Role of PD-1/PD-L1 signaling axis in oncogenesis and its targeting by bioactive natural compounds for cancer immunotherapy

Abstract

Cancer is a global health problem and one of the leading causes of mortality. Immune checkpoint inhibitors have revolutionized the field of oncology, emerging as a powerful treatment strategy. A key pathway that has garnered considerable attention is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1). The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body's immune system. Furthermore, it controls the phenotype and functionality of innate and adaptive immune components. A range of monoclonal antibodies, including avelumab, atezolizumab, camrelizumab, dostarlimab, durvalumab, sinitilimab, toripalimab, and zimberelimab, have been developed for targeting the interaction between PD-1 and PD-L1. These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints. This could contribute to the existing arsenal of anticancer drugs. Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis, promoting tumor cell apoptosis, influencing cell proliferation, and eventually leading to tumor cell death and inhibiting cancer progression. However, there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer. Hence, this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules. Moreover, the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules. Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.

Keywords: Cancer; Crosstalk; Natural compounds; PD-1/PD-L1; Therapeutic targets.

Fig. 1

Schematic diagram of proposed signaling pathway representing PD-1, PD-L1, and their interactions. PD-L1 is an immune checkpoint protein, highly expressed in part of tumor cells, and promotes tumor cell escape from T cells. PD-1 expressed on T-lymphocytes can bind to PD-L1 and inhibit T cell proliferation and activity. IFN-γ derived from tumor-infiltrating immune cells induces transcription of PD-L1 in tumor cells via the JAK/STAT signaling pathway along with NF-κB. MAPK signaling further increased the stability of PD-L1 mRNA, thus higher mRNA and protein levels, leading to increased PD-L1 membrane expression. IL-6 binds to IL-6R, resulting in homodimerization of the signal-transducing receptor subunit and activating the intracellular signaling cascades of JAK, STAT3, MAPK, and PI3K. Pathways converging with c-Jun include MAPK and JNK and their reactivation leads to c-Jun and STAT3 dependent enhancement of PD-L1 expression. YAP1 translocates to the nucleus interacting with transcription factors involved in the transcription of genes associated with cell growth and proliferation. Increased kinase activity of EGFR leads to hyperactivation of downstream signaling pathways including MAPK, PI3K/Akt/mTOR, and IL-6/JAK/STAT3 promoting tumorigenesis. PD-L1 mRNA is translated into PD-L1 protein, which is transported to the cell membrane. Akt protein kinase B, CSN5 constitutive photomorphogenic-9 signalosome 5, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ERK extracellular signal-related kinases, GSK-3β glycogen synthase kinase-3β, HIF-1α hypoxia inducible factor-1α, IFN-γ interferon-γ, IFNR interferon receptor, IKKα inhibitor of nuclear factor-κB kinase α, IKKβ inhibitor of nuclear factor-κB kinase β, IKKγ inhibitor of nuclear factor-κB kinase γ, IL interleukin, JAK Janus kinase, STAT signal transducers and activators of transcription, JNK c-Jun N-terminal kinase, LncRNA long non-coding RNA, MAPK mitogen-activated protein kinase, miR microRNA, mTOR mammalian target of rapamycin, MUC1 mucin 1, NF-κB nuclear factor-κB, PD-L1 programmed cell death ligand 1, PD-L2 programmed cell death ligand 2, PIP2 phosphatidylinositol 4,5-bisphosphate, PIP3 phosphatidylinositol-3,4,5-triphosphate, PI3K phosphatidylinositol 3-kinase, Raf rapidly accelerated fibrosarcoma, Ras rat sarcoma virus, TAK1 transforming growth factor-β-activated kinase 1, TAMs tumor associated macrophages, TNF-α tumor necrosis factor-α, TNFR tumor necrosis factor receptor, Wnt wingless/integrated, Wnt3A Wnt family member 3A, YAP Yes-associated protein, ZEB1 zinc finger E‐box binding homeobox 1, PD-1 programmed cell death protein 1, c-Jun cellular homolog of the viral oncoprotein v-jun, SHP2 Src homology-2 domain-containing protein tyrosine phosphatase-2

Fig. 2

Chemical structures of bioactive anticancer phytochemicals targeting PD-1/PD-L1

Fig. 3

Chemical structures of bioactive anticancer natural compounds from non-plant sources targeting PD-1/PD-L1

Fig. 4

Mechanistic overview of targeting PD-1/PD-L1 by bioactive natural compounds. Various natural compounds inhibit signaling pathways involving JAK-STAT and Ras/Raf. Berberine, for example, decreases PD-L1 and Ki-67 levels while increasing cleaved caspase-3. Apigenin and luteolin inhibit IFN-γ-induced PD-L1 expression and STAT3 phosphorylation. Curcumol reduces HIF-1α and VEGF protein levels, limiting crosstalk between STAT3 and HIF-1α pathways and restricting tumor growth. Evodiamine significantly reduces MUC1-C expression, modulating tumor development. Licochalcone A negatively regulates NF-κB and Ras/Raf/MEK signaling pathways. Erianin regulates Ras, VEGF, and HIF-1α expression, inhibiting tumoral growth. β-elemene inhibits p-Akt expression, while lycopene reduces IL-4 and IL-10 levels, enhancing antitumoral T cell activity. Panaxadiol restores T-lymphocytes’ tumor-killing activity, and sativan and polydatin regulate miRNA levels, controlling tumoral cell cycle pathways. Shikonin leads to CSN5 inactivation, degrading PD-L1, and activating tumor infiltration by T cells. HIF-1α hypoxia-inducible factor 1-α, EGFR epidermal growth factor receptor, ERK extracellular signal-related kinases, IFN-γ interferon-γ, JAK Janus kinase, MUC1 mucin 1, mTOR mammalian target of rapamycin, NF-κB nuclear factor-κB, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, Ras rat sarcoma virus, Raf rapidly accelerated fibrosarcoma, STAT signal transducer and activator of transcription, Syk spleen associated tyrosine kinase, TAMs tumor-associated macrophages, TNF-α tumor necrosis factor-α, THC ( −)-trans-∆9-tetrahydrocannabinol, IκB inhibitor of nuclear factor-κB, CD cluster of differentiation, CSN5 constitutive photomorphogenic-9 signalosome 5, COP9 signalosome subunit 5

Fig. 5

Impact of natural compounds targeting PD-1/PD-L1 on various signaling pathways. AMP adenosine monophosphate, ATP adenosine triphosphate, ERK extracellular signal-related kinases, HIF-1α hypoxia-inducible factor 1-α, IFN-γ interferon-γ, JAK Janus kinase, KRAS Kirsten rat sarcoma viral oncogene homologue, mTOR mammalian target of rapamycin, NF-κB nuclear factor-κB, PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, RTK receptor tyrosine kinase, STAT signal transducer and activator of transcription, Syk spleen associated tyrosine kinase, TLR Toll-like receptors, GPX glutathione peroxidase, PTEN phosphatase and TENsin homolog deleted on chromosome 10, PI3K phosphoinositide 3-kinase, TSC tuberous sclerosis complex, MKK mitogen-activated protein kinase, MAPK mitogen-activated protein kinase, HSP27 heat shock protein 27, GM-CSF granulocyte–macrophage colony-stimulating factor, TGF transforming growth factor, IL interleukin, CD cluster of differentiation, TCR T cell receptor, PPi protein protein interactions, E enzyme, EGCG epigallocatechin gallate, IκB inhibitor of nuclear factor-κB, IKK inhibitor of nuclear factor-κB kinase, Rheb Ras homolog enriched in brain, VEGF vascular endothelial growth factor, Src Src kinase, Sck C-terminal Src kinase, VRAP VEGF receptor associated protein

Fig. 6

An overview of various mechanisms involved in the antitumor effects of natural compounds targeting PD-1/PD-L1. PD-1 programmed cell death protein 1, PD-L1 programmed cell death ligand 1, miR-200c microRNA 200c, STAT signal transducer and activator of transcription, IL interleukin, CSN5 constitutive photomorphogenic-9 signalosome 5, Ki-67 antigen Kiel 67, Ras rat sarcoma virus, MUC1-C mucin 1 C-terminal subunit, IFN-γ interferon-γ, CD8⁺ cytotoxic T cells, PI3K phosphatidylinositol 3-kinase, Foxp3 forkhead box P3, TNF-α tumor necrosis factor-α, NF-κB nuclear factor-κB, MDSCs myeloid-derived suppressor cells