Cancer immunotherapy has garnered promise in tumor progression, invasion, and metastasis through establishing durable and memorable immunological activity. However, low response rates, adverse side effects, and high costs compromise the additional benefits for patients treated with current chemical and biological agents. Chinese herbal medicines (CHMs) are a potential treasure trove of natural medicines and are gaining momentum in cancer immunomodulation with multi-component, multi-target, and multi-pathway characteristics. The active ingredient extracted from CHMs benefit generalized patients through modulating immune response mechanisms. Additionally, the introduction of nanotechnology has greatly improved the pharmacological qualities of active ingredients through increasing the hydrophilicity, stability, permeability, and targeting characteristics, further enhancing anti-cancer immunity. In this review, we summarize the mechanism of active ingredients for cancer immunomodulation, highlight nano-formulated deliveries of active ingredients for cancer immunotherapy, and provide insights into the future applications in the emerging field of nano-formulated active ingredients of CHMs.

Arsenic trioxide (ATO) is approved for treating terminal-stage liver cancer in China. Cryptotanshinone (CT), a STAT3 inhibitor, has exhibited certain anti-tumor potency; however, the use of CT enhanced ATO for treating liver cancer has not been reported. Here we try to elucidate how CT could enhance the efficacy of ATO for treating liver cancer and its correlation to STAT3 in vitro and in vivo. Cell viability of ATO combined with CT was assessed by 1MTT assay. Cell apoptosis induced by ATO combined with CT was detected by Annexin V/PI staining and apoptosis-related proteins were detected by western blotting. STAT3-related proteins were analysis by western blotting analysis and Immunofluorescence assays. Efficacy evaluation of ATO combined with CT on xenograft was carried in nude mice and related proteins were analysis by Immunohistochemistry assays. First we evaluated cell vitality, and our data indicated that the ATO combined with CT showed obvious growth inhibition of Bel-7404 cells compared to ATO or CT alone. Next we found that ATO combined with CT induced cell apoptosis in Bel-7404 cells and upregulated the activation of apoptosis-related proteins cleaved-caspase-3, cleaved-caspase-9, and cleaved-poly(ADP-ribose) polymerase in a time-dependent manner. Next, we found that ATO combined with CT not only inhibited the constitutive levels of phosphorylated-JAK2 and phosphorylated-STAT3Tyr705 but did so in a time-dependent manner. We also found that ATO combined with CT reversed the upregulated expression of phosphorylated-STAT3Tyr705 stimulated by interleukin-6 and downregulated STAT3 direct target genes and the anti-apoptotic proteins Bcl-2, XIAP, and survivin but obviously upregulated the promoting apoptosis proteins Bak,.In vivo studies showed that ATO combined with CT decreased tumor growth. Tumors from ATO combined with CT–treated mice showed decreased levels of phosphorylated-STAT3Tyr705 and the anti-apoptotic protein Bcl-2 but an increased level of pro-apoptotic protein Bax. Our study provides strong evidence that CT could enhance the efficacy of ATO in treating liver cancer both in vitro and in vivo. Downregulation of phosphorylated-STAT3 expression may play an important role in inducing apoptosis of Bel-7404 cells.

Metabolic changes are a major feature of tumors, including various metabolic forms, such as energy, lipid, and amino acid metabolism. Sterol regulatory element binding proteins (SREBPs) are important modules in regulating lipid metabolism and play an essential role in metabolic diseases. In the previous decades, the regulatory range of SREBPs has been markedly expanded. It was found that SREBPs also played a critical role in tumor development. SREBPs are involved in energy supply, lipid supply, immune environment and inflammatory environment shaping in tumor cells, and as a protective umbrella to support the malignant proliferation of tumor cells. Natural medicine and traditional Chinese medicine, as an important part of drug therapy, demonstrates the multifaceted effects of SREBPs regulation. This review summarizes the core processes in the involvement of SREBPs in tumors and provides a comprehensive understanding of the pathways through which natural drugs target the SREBP pathway and regulate tumor progression.

β-Elemene (IUPAC name: (1 S,2 S,4 R)-1-ethenyl-1-methyl-2,4-bis(prop-1-en-2-yl) cyclohexane), is a natural compound found in turmeric root. Studies have demonstrated its diverse biological functions, including its anti-tumor properties, which have been extensively investigated. However, these have not yet been reviewed. The aim of this review was to provide a comprehensive summary of β-elemene research, with respect to disease treatment. β-Elemene-related articles were found in PubMed, ScienceDirect, and Google Scholar databases to systematically summarize its structure, pharmacokinetics, metabolism, and pharmacological activity. We also searched the Traditional Chinese Medicine System Pharmacology database for therapeutic targets of β-elemene. We further combined these targets with the relevant literature for KEGG and GO analyses. Studies on the molecular mechanisms underlying β-elemene activity indicate that it regulates multiple pathways, including STAT3, MAPKs, Cyclin-dependent kinase 1/cyclin B, Notch, PI3K/AKT, reactive oxygen species, METTL3, PTEN, p53, FAK, MMP, TGF-β/Smad signaling. Through these molecular pathways, β-elemene has been implicated in tumor cell proliferation, apoptosis, migration, and invasion and improving the immune microenvironment. Additionally, β-elemene increases chemotherapeutic drug sensitivity and reverses resistance by inhibiting DNA damage repair and regulating pathways including CTR1, pak1, ERK1/2, ABC transporter protein, Prx-1 and ERCC-1. Nonetheless, owing to its lipophilicity and low bioavailability, additional structural modifications could improve the efficacy of this drug. β-Elemene exhibits low toxicity with good safety, inhibiting various tumor types via diverse mechanisms in vivo and in vitro. When combined with chemotherapeutic drugs, it enhances efficacy, reduces toxicity, and improves tumor killing. Thus, β-elemene has vast potential for research and development.

Salvia miltiorrhiza Bunge is a kind of Chinese herbal medicine known for activating blood circulation and removing blood stasis, with the effect of cooling blood and eliminating carbuncles, and has been proven to have the effect of treating tumors. However, the inhibitory effect of Salvia miltiorrhiza Bunge extracts (Diterpenoid tanshinones) on tumors by inhibiting angiogenesis has not been studied in detail. This study aimed to investigate the anti-gastric cancer effect of diterpenoid tanshinones (DT) on angiogenesis, including the therapeutic effects and pathways. This experiment utilized network pharmacology was used to identify relevant targets and pathways of Salvia miltiorrhiza Bunge-related components in the treatment of gastric cancer. The effects of DT on the proliferation and migration of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line HUVECs were evaluated, and changes in the expression of angiogenesis-related factors were measured. In vivo, experiments were conducted on nude mice to determine tumor activity, size, immunohistochemistry, and related proteins. The findings showed that DT could inhibit the development of gastric cancer by suppressing the proliferation of gastric cancer cells, inducing apoptosis, and inhibiting invasion and metastasis. In addition, the content of angiogenesis-related factors and proteins was significantly altered in DT-affected cells and animals. Results suggest that DT has potential as a therapeutic agent for the treatment of gastric cancer, as it can inhibit tumor growth and angiogenesis. It was also found that DT may affect the expression of the angiogenic factor VEGF through the PI3K/Akt/mTOR pathway, leading to the regulation of tumor angiogenesis. This study provides a new approach to the development of anti-tumor agents and has significant theoretical and clinical implications for the treatment of gastric cancer.