Prognostic value of the triglyceride-glucose index in gastric cancer

Abstract

Advanced gastric cancer (GC) remains a high-mortality malignancy despite progress in diagnosis and treatment, including immunotherapy. Reliable prognostic markers are essential for better patient stratification. The triglyceride-glucose (TyG) index, a marker of insulin resistance, has shown promise in various cancers, but its role in GC remains unclear. Yao et al investigated its prognostic value in 300 patients with advanced GC receiving immunotherapy and chemotherapy. Their model, which integrates the TyG index, programmed death-ligand 1 expression, and Eastern Cooperative Oncology Group performance status, underscores the impact of metabolic dysfunction on immune response and treatment efficacy. This letter examines the TyG index’s potential as a prognostic tool in GC and its implications for treatment strategies guided by metabolic and immune factors, as demonstrated in Yao et al research.

Key Words: Gastric cancer; Immunotherapy; Immune response; Prognosis; Triglyceride-glucose index

Core Tip: Gastric cancer (GC) remains a high-mortality malignancy despite advances in diagnostics and treatments. Histopathological and biochemical markers that predict prognosis are crucial for treatment planning and assessing mortality and morbidity risk. Recent studies highlight the prognostic value of the triglyceride-glucose ratio (an indirect indicator of insulin resistance) in various cancer types. However, a deeper understanding of its role in predicting the immunotherapy response in GC is critically needed.

TO THE EDITOR

The link between metabolic syndrome and cancer has received increasing attention in recent years. Its impact on cancer development is complex and influenced by multiple interacting factors[1]. Metabolic syndrome comprises several disorders, including high fasting blood glucose, insulin resistance (IR), hypertension, low high-density lipoprotein cholesterol, and elevated triglyceride levels. IR triggers chronic inflammation, prompting macrophages and leukocytes to proinflammatory cytokines[2]. These factors contribute to the pathogenesis of various cancers, including gastric, pancreatic, and colorectal.

Gastric cancer (GC) is a multifactorial disease influenced by environmental, host, and genetic factors. Key risk factors include Helicobacter pylori infection, diabetes, metabolic syndrome, and lifestyle choices, all of which contribute to carcinogenesis[3]. Numerous studies link obesity to GC pathogenesis, although its exact mechanisms remain unclear, with several theories proposed. IR, a key factor in metabolic syndrome is also recognized as a critical mechanism in gastric carcinogenesis. One hypothesis suggests that hyperinsulinemia resulting from IR leads to elevated insulin-like growth factors (IGFs) and an altered IGF/IGF-binding protein ratio, promoting cell division and inhibiting apoptosis. This, in turn, has the potential to promote cell division and inhibit apoptosis[2]. Furthermore, obesity-induced inflammation, which is mediated by factors such as tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1 contributes to the GC development by stimulating proliferation and inhibiting apoptosis in GC cell lines[4].

The evaluation of IR was undertaken using various methods, including the hyper-insulinemic-euglycemic clamp and the insulin tolerance test. However, the triglyceride-glucose (TyG) index has emerged as a noninvasive surrogate marker for IR, integrating fasting plasma glucose and triglyceride levels[5]. To date, an elevated TyG index has not been significantly linked to GC; however, it could theoretically serve as an independent prognostic marker and potentially increase the risk of gastrointestinal cancer[6]. A study by Kim et al[7] demonstrated a positive correlation between the TyG index and GC risk, suggesting that a higher TyG index is associated with an increased likelihood of developing the disease. This relationship may stem from the shared connection between gastric carcinogenesis, the TyG index, and metabolic syndrome.

The TyG index has been linked to precancerous conditions and may contribute to cancer pathogenesis through IR. However, its impact on chemotherapy response in patients with established cancer remains unclear. Treatment outcomes depend on individual biology, cancer type, therapeutic approach, and immune status. Emerging evidence suggests that metabolic dysregulation—reflected by a higher TyG index—can influence tumor metabolism, the tumor microenvironment, and drug resistance, potentially affecting chemotherapy efficacy. For instance, a study by Yao et al[8] found that higher TyG indices were associated with improved responses to chemotherapy regimens combined with immunotherapies in GC patients. The relationship between metabolic syndrome and the immunotherapy response remains to be fully understood, a high TyG index may enhance the immune response.

A high TyG index may indicate healthier metabolic responses, allowing some patients to better activate their immune system while maintaining favorable metabolic parameters[9]. This finding suggests that the TyG index plays a multifaceted role in immune regulation, potentially promoting healing or regulatory effects. As a result, immune checkpoint inhibitors may be more effective in patients with a high TyG index because of various underlying mechanisms. Advancements in understanding the tumor microenvironment have positioned immunotherapy as a cornerstone in the treatment of advanced GC.

In this retrospective study of 300 patients, Yao et al[8] examined the impact of the TyG index on the mortality in those treated with a combination of chemotherapy and sintilimab. Simtilimab, a monoclonal antibody targeting programmed death protein (PD), helps cancer cells evade immune detection by reactivating T cells for a more effective anti-cancer response[10,11]. The TyG index cut-off for IR is typically between 1.73 and 1.75, although the optimal value—maximizing sensitivity and specificity—has been established at 1.79 in this study[8].

This value is particularly significant for defining IR in patients with obesity and metabolic syndrome, although it may vary by population, age, and geographical region. It may also differ when used to predict disease severity, prognosis, or treatment response. Therefore, further research is needed to establish an optimal clinical cut-off for the TyG index.

In addition to the independent risk factors such as Eastern Cooperative Oncology Group performance status, programmed death-ligand 1 (PD-L1) expression, and the TyG index, as highlighted by Yao et al[8], the choice of chemotherapy regimen may also influence prognosis and survival. During the study, while sintilimab doses remained consistent, chemotherapy regimens (oxaliplatin + S-1, oxaliplatin + capecitabine, docetaxel, and albumin paclitaxel) were adjusted based on the patient’s liver and renal functions, as well as body mass index, in accordance with clinical guidelines.

Some studies indicate that both PD-L1 expression and inflammation are associated with a more robust immune response. In a clinical trial on prostate cancer, Martini et al[12] found that the survival benefit linked to the TyG index may be partly due to the suppression of certain oncogenes, along with increased PD-1 expression and enhanced sensitivity to PD-1 inhibitors. These effects stem from the immunosuppressive influence of obesity, which leads to greater sensitivity to PD-1 inhibitors. Similarly, Yao et al[8] identified PD-L1 expression as an independent prognostic factor for overall survival.

The need for activated immune cells to consume large amounts of glucose is well documented. The TyG index, which reflects glucose metabolism, highlights the role of glycolysis in both rapid ATP production by immune cells and supplying the biosynthetic materials necessary for their growth and proliferation. In tumors, cells often rely on aerobic glycolysis for energy. Therefore, a high TyG index, indicative of IR and reduced glucose utilization, may hinder tumor cell growth.

Alternatively, free fatty acids play a crucial role in regulating T-cell proliferation. Efficient lipid and glucose metabolism, as indicated by a high TyG index, ensures that T cells receive the energy and metabolic precursors to function effectively, potentially mitigating obesity-induced inflammation and IR[13].

As highlighted in this study[8], the TyG index also reflects the patient’s nutritional status and optimal nutritional and metabolic conditions can enhance immunotherapy efficacy by stimulating systemic immune function. Lower blood lipid levels may indicate cachexia or malnutrition, which can lead to a poorer prognosis. Okadome et al[14] suggested that the TyG index may influence the prognosis of esophageal cancer, emphasizing that a patient’s systemic nutritional and immunological status could affect their prognosis through local tumor immunity. Similarly, a retrospective study of 896 GC patients who underwent curative resection found that prognosis significantly varied based on factors such as age, TyG index, serum hemoglobin and albumin levels, tumor location, laparoscopic surgery, surgical procedure, reconstruction type, combined resection, TNM stage, histological type, and postoperative complications[15]. These findings support the notion that beyond tumor biology and stage, a patient’s nutritional status (hemoglobin and albumin values, TyG index) is closely linked to treatment responses and survival, as demonstrated in the study by Yao et al[8].

Conclusion

This study is particularly significant because it comprehensively examined the impact of the TyG index on the efficacy of immunotherapy combined with chemotherapy in patients with advanced GC. The results contributed to a predictive model for comparing long-term prognoses. The findings appear contradictory, given that IR and metabolic syndrome are known to contribute to the development of various malignancies. This discrepancy stems from the heterogeneity of patient groups, differences in tumor stages, and variations in tumor biology. Moreover, IR may in some cases, positively influence cancer treatment responses, potentially affecting the effectiveness of therapies such as immunotherapy. As a result, the TyG index holds promise as a predictive tool. However, further research is needed to better understand its role in cancer prognosis and treatment outcomes.