Gastric cancer (GC) is one of the most common cancer type in China, and newly diagnosed cases increased from 403,000 in 2015 to 479,000 in 2020 (1). It remains the fourth leading cause of cancer mortality worldwide (2). A large portion of patients with GC do not respond to conventional therapies or are at a higher risk for recurrent disease after they received those interventions, such as perioperative chemotherapy or chemotherapy alone (3,4) and anti-HER2 agent trastuzumab in combination with chemotherapy (5).

Over the last decade, the tumor microenvironment (TME) has become a hot topic for overcoming treatment failure or resistance to current therapies for advanced cancer, including GC (6–8). Various studies have evidenced promising outcomes in patients with GC through targeting angiogenesis, immune suppression and normalization of the tumor-permissive environment (9–15). The Xiaotan Sanjie decoction, a traditional Chinese medicine (TCM) regimen, is composed of 11 traditional medicinal components (16), formulated according to the phlegm syndrome theory (17). Phlegm syndrome, a TCM term, is used to diagnose patients with diseases caused by phlegm (harmful products originated from dysfunctional body fluid circulation) characterized by symptoms and signs including lack of appetite, nausea, vomiting, feel of heavy body, oily looking skin on the face and a pale tongue (18,19). Phlegm syndrome is prevalent in patients with GC (17). Previous preclinical studies have shown that the Xiaotan Sanjie decoction has the ability to regulate levels of some cytokines, growth factors and receptors, such as interleukin-8 (IL-8) (20), transforming growth factor-β (TGF-β) (21), TGF-β receptor 2 (TGFBR2) (22) and CD44V6 (23) in the TME of GC. The Xiaotan Sanjie decoction shows favorable antitumor activities (24) and clinical outcomes (25) in patients with GC.

The TME may constitute the biological basis of phlegm syndrome in patients with GC. We hypothesized that TME in GC may redefine the phlegm syndrome by way of current biomolecular approaches. A literature review was performed to explore the association between phlegm syndrome and the TME, and what roles treatment with the Xiaotan Sanjie decoction played in the management of patients with GC in regard to target components, including cancer-associated fibroblasts (CAFs), extracellular matrix (ECM) and the erratic tumor vasculature within the TME. A preliminary literature search for the Xiaotan Sanjie decoction and TME related articles was performed on the PubMed (https://pubmed.ncbi.nlm.nih.gov/), ScienceDirect (https://www.sciencedirect.com/), Google Scholar (https://scholar.google.com/) and CNKI (https://www.cnki.net/). The following key search terms and phrases were used in combination or separately: ‘Xiaotan Sanjie’, ‘Jinlongshe’ (hospital prepared formulation of Xiaotan Sanjie decoction), ‘phlegm’, ‘phlegm syndrome’, ‘gastric cancer’, ‘tumor microenvironment’, ‘cancer-associated fibroblasts’, ‘extracellular matrix’, ‘transforming growth factor-β’, ‘tumor vasculature’ and ‘angiogenesis’. This may promote translation of TCM theories into modern molecular landscape.

For >2,000 years, TCM has established a tradition of interpreting diseases and making therapeutic decisions (26). TCM syndrome (pronounced ‘Zheng’ in Chinese), a TCM term, is a combination of the presentation, pathogenesis, site and development tendency of a disease at a specific stage during its course) is based on the gathering of general manifestations of patients through inspection, hearing, inquiry and taking pulse, which is the essential diagnostic process by which TCM physicians describe signs and symptoms and make a treatment plan (27,28). ‘Phlegm syndrome’ is an important type of ‘syndrome’ in TCM. Zhenheng Zhu, a famous TCM physician from the Yuan dynasty (1,279–1,368 AC), said that 9/10 diseases were caused by phlegm (29). TCM has two general types of phlegm: Internal and external (nasal discharge or sputum from respiratory tract) (30). In TCM it is considered that the internal phlegm will arise when the body's fluid metabolism is disturbed by intrinsic or extrinsic factors, such as qi deficiency, qi stagnation, stagnancy of dampness, climatic factors, emotional changes and improper diet (31). The internal phlegm may accumulate in Zang and Fu viscera to disrupt the normal functions of the organs and systems or circulate via meridians and collaterals to distant organs from its source (30). The characteristics of phlegm syndrome can be observed in numerous disorders, including poor general status, respiratory diseases, gastrointestinal disorders, cardiovascular diseases, overweight, neurological dysfunctions and cancer (31).

Numerous major risk factors can be observed in patients with phlegm syndrome and GC concurrently. Improper dietary behaviors take prominent part in the development of phlegm syndrome and GC, such as excessive consumption of pickled or salted food or roasted and greasy foods (17). Overeating itself is also a cause of phlegm (32). H. pylori infection increases the risk of GC; moreover, salted food consumption may further promote H pylori infection, and jointly participate in the development of GC (33). Aging, obesity and chronic inflammation are all commonly found in patients with phlegm syndrome and in patients with GC (32).

GC is characterized by heterogeneous pathology in regard to anatomical location and histological subtypes (33). GC may be detected in almost all parts of the stomach, especially in the lower region (34). GC cells may move from their original site to distant body parts by way of the blood or lymphatic vessels with advancing stages of the disease in patients with GC (35). A broad range of locations should be noted in the diagnostic process, including the abdominal cavity, liver, supraclavicular lymph node, ovaries and umbilical region and Blumer shelf (a mass in the perirectal pouch) (36). Correspondingly, phlegm syndrome presents as a dynamic evolutionary process similar to GC development (32). Phlegm can also be categorized into substantial and insubstantial. Substantial phlegm is visible and palpable, such as scrofula and nodules in the skin and muscles (29). When accumulating, the phlegm is substantial; when dispersing, the phlegm is insubstantial (32). Phlegm arising in the spleen can easily extend to or accumulate in almost all other parts of the body (31), which is referred to as ‘phlegm evil flowing’ in TCM (32). Phlegm may play an important role in the pathogenesis and metastases of GC. Accumulation of internal phlegm transforms from an insubstantial to a substantial phlegmatic nodule in the stomach, and a phlegmatic nodule may create a vicious phlegmatic environment in which it will release more phlegm to relocate to other parts of the body (32).

The Xiaotan Sanjie decoction is prepared to relieve symptoms and signs of phlegm syndrome in patients with GC. The Xiaotan Sanjie decoction is mainly composed of Pinelliae rhizome, Arisaematis rhizoma, Scorpio, Scolopendra, baked Endothelium corneum gigeriae galli, prepared Glycyrrhiza uralensis Fisch and other natural products (Table I). Pinelliae rhizoma and Arisaematis rhizoma are the dominant ingredients to dry dampness and resolve phlegm, prevent nausea and vomiting, relieve pain and dissolve lumps and resolve masses. Scorpio, Scolopendra and baked Endothelium corneum gigeriae galli are second principal medicinal components to activate the meridians, relieve pain and eliminate phlegmatic nodules. The prepared Glycyrrhiza uralensis Fisch plays a coordinator role to direct other medicines to the sites where affected by phlegm, to reduce toxicity and to improve flavor (37). All of these natural products work synergistically together to improve overall physical status of the patients with GC, especially in patients with advanced disease (17). TCM usages, active compounds and antitumor effects of each component in the Xiaotan Sanjie decoction are described and summarized in a non-exhaustive list in Table I.

Malfunctioned vascular structures and ECM create a hostile metabolic and mechanical TME that is characterized by hypoxia, low pH and high interstitial pressure (38). Tumors become infiltrated with immune and inflammatory cells (39–41), blood endothelial cells (42), lymphatic endothelial cells (6), CAFs (43), the ECM (44) and bone marrow-derived mesenchymal stem cells (8) within the stroma. Crosstalk exists between tumor-associated stromal cells and tumor cells through signaling molecules to promote tumor invasion, metastasis, immunosuppression and to induce treatment resistance (45). Regulation of the active interaction between tumor cells and tumor-associated stromal cells (that interfere with IL-6 mediated crosstalk between tumor cells and CAFs) in the TME has shown promising antitumor effects in GC (46). The Xiaotan Sanjie decoction, a decoction that contains a plethora of phytochemical compounds (47–49), vitamins (50), and peptides (51–53) has demonstrated multiple actions on various soluble molecules, cytokines and growth factors released by parenchyma and stroma cells of GC. The Xiaotan Sanjie decoction shows activities on desmoplastic reactions (21,54,55), ECM formation and degradation (56,57), and tumor blood supply (58–61) through regulating these elements in the TME over the course of the GC progression.

The Xiaotan Sanjie decoction has been used to treat GC with good efficacy and safety profile for >20 years (17,32). The Xiaotan Sanjie decoction improves quality of life more compared with chemotherapy in patients with advanced GC who had undergone the subtotal or total gastrectomy proceedure (107–109). The Xiaotan Sanjie decoction has shown satisfactory outcomes in clinical studies that evaluated the effects of the decoction in combination of chemotherapy or other Chinese medicinal formulations on quality of life and overall survival in patients with advanced GC (110–113). In a clinical study, among patients with stage III and IV GC, those who were treated with the Xiaotan Sanjie decoction in combination with chemotherapy (Etoposide, Calcium Folinate and 5-Fluorouracil) had longer overall survival and 3-year survival compared with those who received chemotherapy only (110). In another study, efficacy of Xiaotan Sanjie decoction combined with Huangqi injection and Huachansu injection (both are traditional Chinese patent medicine) were observed in patients with advanced GC. The results showed that TCM can improve Karnofsky performance score, NK cell activity and CD3 and CD4 cells counts more compared with those of chemotherapy (5-Fluorouracil, Oxaliplatin, Vincristine, Cisplatin, Mitomycin) (111). The Xiaotan Sanjie decoction has been shown to have a well-established safety profile, provide an enhanced quality of life, improve tumor response and prolong survival time and Karnofsky performance score in patients with GC (112,113). Therefore, Xiaotan Sanjie decoction may be a promising candidate for use in collaboration with conventional treatment regimens as an alternative method to delay cancer progression.

The TME in GC is a complex ecosystem that consists of newly formed blood and lymphatic vessels and diversified stromal cell types embedded in a modified ECM (8). Targeting the TME has revealed promising survival outcomes by inhibition of VEGF signaling pathway or PD1 signaling pathway in patients with GC (9–11). However, there is a gap between the complete understanding of the underlying molecular mechanisms of a plethora of interconnected molecules and pathways in the TME in GC and exactly how metastatic GC leads to death. More pivotal molecular pathways or cell types need to be revealed in the TME in GC to develop innovative therapeutic regimens.

For thousand years, Chinese physicians have used traditional natural medicine to treat a plethora of diseases, including GC. TCM formulations have notable effects on multiple targets and seldomly cause the occurrence of undesirable effects (26,28). In addition, they may provide long-term benefits for patients with GC (19). The therapeutic effect of TCM formulations on tumors has been demonstrated in multiple pathways, providing reasonable evidence for the ability to restore abnormal TME in GC back into balance (32). For >20 years, models have been established based on phlegm syndrome theory for GC (17). The biochemical properties of the TCM term ‘phlegm’ in GC may be partly described in modern medical language by way of a series of preclinical studies.

Contaminated phlegm is likely to be an important pathological product in the development of GC (114). The hypothesis regarding symptoms, signs and molecular profiles stems from the clinical and experimental observation that the TME in GC can share commonalities with phlegm syndrome (17,32,114). A TCM decoction, Xiaotan Sanjie decoction, has been formulated to treat the phlegm syndrome in patients with GC (17,32). As discussed, the Xiaotan Sanjie decoction has shown activities on CAFs (21,54,55,65), ECM (23,56,57,99,100,104) and the tumor blood supply (58–61) within the TME during tumorigenesis, growth and migration of GC in preclinical studies.

The Xiaotan Sanjie decoction inhibits GC initiation by upregulating TGFBR2 to normalize the antitumor action of the TGF-β/SMAD signaling pathway (22). At subsequent stages, the Xiaotan Sanjie decoction has revealed the ability to decrease the formation of CAFs through interruption of the expression of TGF-β (21). In the single-component studies, the aqueous extracts of Fritillariae cirrhosae bulbus (54) and Sinapis semen (55), two herbal medicinal compositions of Xiaotan Sanjie decoction, suppress the protumorigenic activity of TGF-β/SMAD signaling pathway. In addition, the aqueous extracts of scorpion-medicated serum significantly alleviates the TGF-β1-induced EMT process (81). The Xiaotan Sanjie decoction interferes with crosstalk between CAFs and tumor cells by downregulating IL-6 (83) and IL-8 (20,89) to inhibit tumor proliferation. Isolated compounds extracted from Galli gigerii endothelium corneum (84) and Glycyrrhiza uralensis Fisch (85), another two natural products in the Xiaotan Sanjie decoction, have the ability to downregulate expression of IL-6. Furthermore, the Xiaotan Sanjie decoction alleviates the development of deposition of ECM by blocking the activities of CAFs. The Xiaotan Sanjie decoction interrupts HA-CD44 interaction between ECM and tumor cells by degrading HA (99,100) and downregulating expression of CD44V6 (23,104). The Xiaotan Sanjie decoction has also been revealed to potentially target angiogenesis by downregulating the expression level of VEGF to exert antitumor effects (58–60). During advanced stages, the Xiaotan Sanjie decoction has demonstrated effects on GC tumor cell migration by preventing the degradation of the ECM and its basement membrane (56,57). The possible mechanisms of antitumor activities of the Xiaotan Sanjie decoction are summarized in Fig. 1.

The Xiaotan Sanjie decoction improves survivorship and quality of life in patients with advanced GC in clinical studies. However, it is difficult to compare these clinical outcomes to studies conducted to observe efficacy and safety of synthetic drugs or biological products in patients with GC because the sample size of clinical studies using the decoction is relatively small. Well-designed, prospective, large-scale clinical trials should be conducted to find the most appropriate niche of the Xiaotan Sanjie decoction in the treatment of patients with GC. However, a preliminary conclusion may be drawn that the Xiaotan Sanjie decoction targets CAFs, ECM and angiogenesis in the TME, and thereby the decoction prepared a preferable physical condition for chemoradiation therapy or immune therapy. Advanced technologies, including synthetic biology and scalable spatial analysis of the TME (115,116), are enabling novel methods for finding and exploiting the medicinal value of natural products. Therefore, this has the potential to define the conclusive role of the Xiaotan Sanjie decoction in the treatment of GC.