Prognostic value of the triglyceride-glucose index in advanced gastric cancer: A call for further exploration

Abstract

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, necessitating the identification of reliable prognostic indicators to enhance treatment outcomes. Recent research has highlighted the triglyceride-glucose (TyG) index as a potential surrogate marker for insulin resistance, which may significantly influence the prognosis of patients undergoing immunotherapy combined with chemotherapy. In this context, the study by Yao et al demonstrates that a high TyG index correlates with improved overall survival and progression-free survival in advanced GC patients receiving sintilimab and chemotherapy. Specifically, patients in the high TyG group had a significantly longer median progression-free survival of 9.8 months [95% confidence interval (CI): 9.2-10.9] compared to 8.0 months (95%CI: 7.5-8.5) in the low TyG group (hazard ratio = 0.58, 95%CI: 0.43-0.79, P < 0.001). Similarly, the median overall survival was significantly longer in the high TyG group at 23.1 months (95%CI: 21.2-NA) vs 16.5 months (95%CI: 13.9-18.3) in the low TyG group (hazard ratio = 0.30, 95%CI: 0.21-0.42, P < 0.001). These findings underscore the strong prognostic potential of the TyG index in guiding treatment strategies for advanced GC. These findings underscore the need for further investigation into the TyG index’s role as a prognostic tool and its underlying mechanisms in influencing treatment efficacy. We advocate for additional multicenter studies to validate these results and explore the TyG index’s applicability across diverse patient populations, ultimately aiming to refine treatment strategies and improve patient outcomes in advanced GC.

Key Words: Advanced gastric cancer; Chemotherapy; Insulin resistance; Prognostic marker; Triglyceride-glucose index; Tumor microenvironment

Core Tip: The triglyceride-glucose (TyG) index, a surrogate marker for insulin resistance, has emerged as a potential prognostic factor in advanced gastric cancer. Recent findings suggest that a high TyG index correlates with improved overall survival and progression-free survival in patients undergoing immunotherapy combined with chemotherapy. This highlights the clinical relevance of insulin sensitivity in modulating treatment efficacy. Further multicenter studies are essential to validate its prognostic value across diverse populations and to explore underlying mechanisms. Integrating the TyG index into comprehensive prognostic models may optimize treatment strategies and improve patient outcomes in advanced gastric cancer.

TO THE EDITOR

We are writing to discuss the insightful article by Yao et al[1], recently published. This study presents a significant advancement in our understanding of prognostic factors in advanced gastric cancer (GC), particularly in the context of emerging immunotherapeutic strategies.

SIGNIFICANCE OF THE TYG INDEX

The triglyceride-glucose (TyG) index is calculated using fasting triglyceride and fasting glucose levels, following the formula: TyG = ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2], serves as a surrogate marker for insulin resistance[2]. Insulin resistance has been implicated in various malignancies, including GC, where it may promote tumorigenesis through several mechanisms such as enhanced cellular proliferation, increased angiogenesis, and immune evasion[3]. The findings from Yao et al[1] indicating that a high TyG index correlates with improved overall survival (OS) and progression-free survival in patients undergoing treatment with sintilimab and chemotherapy are particularly noteworthy. Specifically, their study reported that patients with a high TyG index (≥ 1.79) had a significantly longer median progression-free survival of 9.8 months [95% confidence interval (CI): 9.2-10.9] compared to 8.0 months (95%CI: 7.5-8.5) in the low TyG index group (< 1.79) [hazard ratio (HR) = 0.58, 95%CI: 0.43-0.79, P < 0.001]. The median OS was also significantly extended in the high TyG index group, reaching 23.1 months (95%CI: 21.2-NA) compared to 16.5 months (95%CI: 13.9-18.3) in the low TyG index group (HR = 0.30, 95%CI: 0.21-0.42, P < 0.001). In multivariate analysis, the TyG index was identified as an independent prognostic factor for OS (HR = 0.36, 95%CI: 0.24-0.55, P < 0.001), further reinforcing its predictive value. These results suggest that metabolic status, as reflected by the TyG index, plays a crucial role in shaping treatment outcomes in advanced GC. This relationship suggests that insulin sensitivity may play a role in modulating the efficacy of immunotherapy, potentially influencing treatment outcomes[1,3].

CLINICAL IMPLICATIONS

The TyG index has shown significant prognostic value in advanced GC, with Yao et al[1] reporting a notable survival benefit in patients with a high TyG index (median OS: 23.1 months vs 16.5 months, HR = 0.30, P < 0.001)[2]. These findings suggest that metabolic profiling could serve as an additional stratification tool in clinical decision-making, allowing for more tailored treatment strategies. Integrating the TyG index into prognostic models alongside established biomarkers, such as programmed death-ligand 1 (PD-L1) expression and electrocorticography performance status, may refine patient selection for intensive therapeutic regimens, particularly in combination with immunotherapy[4,5].

Given the mechanistic links between insulin resistance and immunotherapy response, the TyG index may also help predict immune checkpoint inhibitor efficacy. Insulin resistance, through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, promotes tumor growth and alters the tumor microenvironment, contributing to immune suppression and metabolic competition. Patients with a high TyG index, indicative of metabolic dysregulation, may benefit from adjunctive metabolic interventions (e.g., metformin or mTOR inhibitors) to enhance their responsiveness to immunotherapy[1]. Additionally, the predictive role of the TyG index in identifying patients at risk of immune exhaustion due to metabolic competition warrants further investigation[6,7].

Future research should explore whether metabolic modulation strategies could synergize with immune checkpoint blockade to improve patient outcomes. For example, patients with a high TyG index could be prioritized for intensive therapeutic regimens or innovative treatment approaches, while those with lower indices might benefit from closer monitoring or alternative therapeutic options. Such stratification could ultimately contribute to enhanced survival outcomes and improved quality of life for affected patients[1,8,9].

MECHANISTIC INSIGHTS

This study paves the way for deeper investigation into the biological mechanisms connecting insulin resistance with cancer progression and treatment response[10,11]. Insulin resistance is known to activate multiple oncogenic signaling pathways, notably the PI3K/Akt/mTOR pathway[12]. This pathway regulates cellular metabolism, proliferation, and survival, and its dysregulation is implicated in cancer progression and therapeutic resistance. Persistent insulin resistance leads to chronic activation of PI3K/Akt signaling, promoting tumor growth and impairing the efficacy of immune checkpoint inhibitors by fostering an immunosuppressive environment[13]. Hyperactivation of mTOR can also reduce T-cell function, limiting the anti-tumor immune response[14,15]. Given the intricate interplay between metabolic dysfunction and GC progression, we summarize the key metabolic factors associated with the TyG index and their respective effects in Table 1.

Table 1 The Role of the triglyceride-glucose index in metabolic dysfunction and gastric cancer progression.

Metabolic factor	Associated changes	Impact on gastric cancer
Insulin resistance	↑ PI3K/Akt/mTOR activation, ↑ growth signals, ↓ apoptosis	Promotes tumor proliferation and therapy resistance
Lipotoxicity	↑ Free fatty acids, ↑ IL-6/TNF-α, ↑ inflammation	Enhances pro-tumor immune suppression
Glucotoxicity	↑ Oxidative stress, ↑ DNA damage, ↑ chronic inflammation	Facilitates tumor progression and metastasis
Altered TME	↑ Metabolic competition (glucose depletion), ↓ T-cell function	Reduces efficacy of immunotherapy
Hyperlipidemia and obesity	↑ Systemic inflammation, ↑ lipid metabolism dysfunction	Alters immune response, may influence prognosis

PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; TME: Tumor microenvironment; IL: Interleukin; TNF: Tumor necrosis factor.

Additionally, insulin resistance influences the tumor microenvironment through multiple mechanisms. First, it enhances systemic and local inflammation via upregulation of pro-inflammatory cytokines (e.g., interleukin-6, tumor necrosis factor-α), which can create an immunosuppressive niche[10,16,17]. Second, the altered metabolic landscape associated with insulin resistance leads to increased competition for glucose between tumor cells and immune cells, particularly T cells. Since effector T cells rely heavily on glycolysis for energy, metabolic competition in an insulin-resistant state may result in T-cell exhaustion and impaired anti-tumor immunity. Finally, increased circulating insulin levels can stimulate the expression of PD-L1 on tumor and immune cells, potentially affecting the response to programmed death 1/PD-L1 blockade therapies[18,19]. Future research should focus on unraveling these intricate pathways and exploring their interactions with immunotherapeutic agents, such as sintilimab, to enhance our understanding and improve therapeutic outcomes.

NEED FOR MULTICENTER STUDIES

While the study by Yao et al[1] presents compelling evidence, the importance of multicenter studies cannot be overstated[20]. Such investigations are crucial for improving the generalizability of the findings across diverse populations and clinical settings[21]. Differences in genetic backgrounds, lifestyle factors, and comorbidities can profoundly impact both insulin resistance and cancer biology. Consequently, validating the TyG index as a prognostic tool in heterogeneous cohorts will be indispensable for confirming its applicability and reliability in routine clinical practice.

FUTURE DIRECTIONS

Future investigations should aim to integrate the TyG index with other biomarkers and clinical parameters to construct a more comprehensive prognostic model. Such models could include factors such as tumor staging, histological subtypes, and molecular characteristics, offering a more nuanced and holistic perspective on patient prognosis.

CONCLUSION

In conclusion, I commend Yao et al[1] for their valuable contribution to advancing our understanding of prognostic markers in advanced GC. The TyG index emerges as a promising tool for improving patient stratification and optimizing treatment strategies in this challenging clinical domain. Further research into the utility of this biomarker and its potential incorporation into routine clinical practice is essential to enhance outcomes for patients with advanced GC.