## 3 Preclinical Evidence Evaluating the Effects of Phytochemicals on Immune Checkpoints
These observations show that different phytochemicals could act differently on STAT proteins (immune-activating vs. immune-suppressive), and various classes of phytochemicals (i.e., flavonoid and non-flavonoid polyphenols) could have different potency on the tumor immune milieu (Figure 2). Further delineation of these interactions for individual phytochemicals is paramount to designing successful phytochemical and immunotherapy combinations. Figure 2: Schematic figure reporting the main phytochemicals which have been tested as modulators of immune checkpoint inhibitors in cancer patients. The flavonoid polyphenols include, among others, icaritin, luteolin, bilberry anthocyanin, and melafolone. Non-flavonoid polyphenic compounds include curcumin, gallic acid, gallotannin, and resveratrol, while terpen include lycopene, diosgenin, and cryptotanshinone. \begin{table}
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**Authors** & **Prystochemical Group** & **Prystochemical Group** & **Immune Chevelopant Inhibitor** & **Cancer Type** & **Cancer Model** & **Mechanism of Effect** & **Outcome** \\ \hline [PERSON] et al. (2017)[27] & Non-flavored polyphenols & Cucurmin & Anti-PD-1 antibody (200 ig) & Bladder Cancer & MB9 bladder carcinoma & - Increase intraterminal CDS T-cell & Prolonged survival of intraperitoneal \\ \hline [PERSON] et al. (2017)[27] & Non-flavored polyphenols & Cucurmin & Anti-PD-1 antibody (50 mg/kg) & Chick & C72 colorectal tumor-bearing & Reduce the expression of PD-1L, and PD2L, and CDC & Reduce tumor growth \\ \hline [PERSON] et al. (2020)[28] & Non-flavored polyphenols & Cucurmin & Anti-PD-1 antibody (  
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**Authors** & **Hypochemical Group** & **Hypochemical Compound** & **Hypochemical Compound** & **Immune Checkpoint Inhibitor** & **Cancer Type** & **Cancer Model** & **Mechanism of Effect** & **Outcome** \\ \hline [PERSON] (2019) (25) & Non-flavored polyphenols & Revertural Anti-PD-1 antibody (10 mg/kg) & & Anri-PD-1 antibody (10 mg/kg) & Ovarian Cancer & Human ovarian carcinoma oil lines (SKOV3 and A7280) and murine carcinoma oil line (IDS) & Induction of tumor oil apoptosis line (IDS) & Reduce tumor growth line \\ \hline [PERSON] et al. (2021) & Flavored & Latetin & Antichin Origin & Anri-PD-1 antibody (10 mg/kg) & NSCLC & KRAS-mutant human lung cell lines (IDS) (IDS, H408, H42122, and A549) and mice in vivo mode & Down-regulated the INN-induced response by expressing the phosphorylation of STAT3 \\ [PERSON] et al. (2020) & Flavored (2016) & Bilvery Antomyosin & & Anri-PD-11 antibody (200 mg/kg) & CRC & MC-30 colorectal tumour-bearing & Modulate the gut microbiome & Tumor growth delay \\ \hline [PERSON] et al. (2021) & Flavored & Leartin & Anti-PD-1 antibody (10 mg/kg) & HCC, CRC, and melanoma & Human hepatocellular maker carcinoma, colorectal cancer and melanoma cell lines (H2 FAI-6) and M-5-B6 & Down-regulate PDL-1 expression and H-5-B6 & Reduce the tumor volume and weight in vivo mode \\ \hline [PERSON] et al. (2019) & Flavored & Melikolome & Anti-PD-1 Abs (200 mg/kg) & Lung Cancer & [PERSON] lung carcinoma or CMT tumor-bearing C57N/6 \(\pm\) mice & Down-regulate VIGER, TCF-8, and PD-11 through COX-2 and EGFR inhibition & Pumped survival function \\ \hline [PERSON] et al. (2019) & Terpones & Lycopene & Anri-PD-1 antibody (6 mg/kg) & Lung Cancer & [PERSON] lung carcinoma & Increase IFN levels  
Preclinical Studies Evaluating the Efficacy of Phytochemical and Immune Checkpoint Inhibitor Combinations  
Several studies have evaluated the efficacy of ICI plus phytochemicalominal combinations using variable phytochemicals in different cancer models (Table 2). The first report of a phytochemicalomical and ICI combination strategy (bisdemethoxycurumin with an anti-PD-L1 antibody) was published by [PERSON] et al. in 2017 in a mouse bladder cancer model [27].