Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy

Abstract

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.

Remodeling tumor microenvironment with natural products to overcome drug resistance

“…A study on traditional Chinese medicine anti-tumor found that three typical natural products of Huangqin, oroxylin A, wogonin and baicalin, may overcome anti-cancer drug resistance by modulating the tumor immunosuppressive microenvironment ( 233 ). Natural products modulate immune checkpoint-related signaling molecules via multiple signaling cascades in the tumor microenvironment combined with immune checkpoint inhibitors (ICIs), which not only enhance the effectiveness of immunotherapy but also reduce the adverse effects of resistance ( 234 ). Signal transducer and activator of transcription 3 (STAT3) hyperactivation regulates immune responses in the tumor microenvironment by cytokines, growth factors, and G protein-coupled receptors to attenuate drug resistance and control cancer metastasis ( 235 ).…”

Genetic Heterogeneity, Tumor Microenvironment and Immunotherapy in Triple-Negative Breast Cancer

“…Current research on this subject is focused on combining immune checkpoint inhibition with chemotherapy, PARP inhibitors, cancer vaccines, or NK cell therapy [ 128 ]. Furthermore, nutraceuticals are commonly used in the prevention and treatment of TNBC because plant-based food rich in phytochemicals can effectively modulate immune checkpoint-related signaling molecules such as PD-1 / PD-L1 [ 129 , 130 ]. Moreover, specifically designed nanoparticles with ligands on their surface can facilitate drug delivery by targeting to cancer cells to, for example, modulate immune responses.…”

Inhibition and potential treatment of colorectal cancer by natural compounds via various signaling pathways

“…At present, natural compounds have been shown to modulate intracellular biochemical reactions including the regulation of immune checkpoints such as PD-L1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4), through a variety of signaling pathways. These effects have been confirmed in multiple cancer types including colon cancer ( 219 ). Previous studies have revealed that NF-κB, PI3K and MAPK signaling pathways were involved in the regulation of CRC via PD-L1 by resveratrol, piceatannol and panaxadiol ( 22 , 220 ).…”