Background <p>Lung cancer remains a leading cause of cancer-related mortality globally. Although immunotherapy with anti-PD-1 monoclonal antibodies has revolutionized treatment, its efficacy is often limited by acquired resistance and a low response rate. The gut microbiota (GM) and endoplasmic reticulum stress (ERS) have emerged as crucial factors influencing the tumor microenvironment and immune responses. Traditional Chinese Medicine (TCM), such as Shuyu Pills (SYP), is being explored for its potential to enhance immunotherapy. This study aimed to investigate the mechanism by which SYP enhances the efficacy of anti-PD-1 therapy in lung cancer, specifically focusing on the “GM-ERS-Immunity” axis.</p> <p>Aim of the study This study aimed to systematically elucidate how the TCM formula Shuyu Pills (SYP) enhances anti-PD-1 mAb therapy in lung cancer by integrating network pharmacology and in vivo validation.</p> Methods <p>We established a lung cancer mouse model and treated the mice with SYP, anti-PD-1 monoclonal antibodies, or a combination of both. Tumor growth was monitored, and immune responses were assessed by flow cytometry. To investigate the underlying mechanism, we performed gut microbiota sequencing (16 S rRNA sequencing) and analyzed key markers associated with endoplasmic reticulum stress (ERS) and immunity. Network pharmacology was employed to identify the active components of SYP and their potential targets.</p> Results <p>We established a lung cancer mouse model and treated the mice with SYP, anti-PD-1 monoclonal antibodies, or a combination of both. Tumor growth was monitored, and immune responses were assessed by flow cytometry. To investigate the underlying mechanism, we performed gut microbiota sequencing (16 S rRNA sequencing) and analyzed key markers associated with endoplasmic reticulum stress (ERS) and immunity. Network pharmacology was employed to identify the active components of SYP and their potential targets.</p> Conclusions <p>This study reveals a novel mechanism by which the traditional Chinese medicine formula, SYP, enhances the therapeutic efficacy of anti-PD-1 in lung cancer. By regulating the gut microbiota and subsequently alleviating endoplasmic reticulum stress, SYP potentiates the host’s anti-tumor immunity. These findings provide a strong theoretical basis for the clinical application of SYP as an adjunctive therapy to overcome resistance and improve the effectiveness of anti-PD-1 immunotherapy.</p> Graphical Abstract <p></p>

A Novel Strategy for Enhancing Lung Cancer Immunotherapy Efficacy: Traditional Chinese Medicine Formula Shuyu Pills Enhances Anti-PD-1 Efficacy Via the “GM-ERS-Immunity” Axis

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2025年12月3日

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Sheng Chen,
Jing Wen,
Zhengyi Liu,
Yuxiang Hu,
Chenhong Zhu,
Xiao Yang,
Zhi Wen,
Cai Tan,
Yaoyao Li,
Anqi Xiao,
Shuying You,
Tonglin Sun,
Hua Liu,
Yinhui Sun,
Lihuai Wang

摘要

Background

Lung cancer remains a leading cause of cancer-related mortality globally. Although immunotherapy with anti-PD-1 monoclonal antibodies has revolutionized treatment, its efficacy is often limited by acquired resistance and a low response rate. The gut microbiota (GM) and endoplasmic reticulum stress (ERS) have emerged as crucial factors influencing the tumor microenvironment and immune responses. Traditional Chinese Medicine (TCM), such as Shuyu Pills (SYP), is being explored for its potential to enhance immunotherapy. This study aimed to investigate the mechanism by which SYP enhances the efficacy of anti-PD-1 therapy in lung cancer, specifically focusing on the “GM-ERS-Immunity” axis.

Aim of the study This study aimed to systematically elucidate how the TCM formula Shuyu Pills (SYP) enhances anti-PD-1 mAb therapy in lung cancer by integrating network pharmacology and in vivo validation.

Methods

We established a lung cancer mouse model and treated the mice with SYP, anti-PD-1 monoclonal antibodies, or a combination of both. Tumor growth was monitored, and immune responses were assessed by flow cytometry. To investigate the underlying mechanism, we performed gut microbiota sequencing (16 S rRNA sequencing) and analyzed key markers associated with endoplasmic reticulum stress (ERS) and immunity. Network pharmacology was employed to identify the active components of SYP and their potential targets.

Results

We established a lung cancer mouse model and treated the mice with SYP, anti-PD-1 monoclonal antibodies, or a combination of both. Tumor growth was monitored, and immune responses were assessed by flow cytometry. To investigate the underlying mechanism, we performed gut microbiota sequencing (16 S rRNA sequencing) and analyzed key markers associated with endoplasmic reticulum stress (ERS) and immunity. Network pharmacology was employed to identify the active components of SYP and their potential targets.

Conclusions

This study reveals a novel mechanism by which the traditional Chinese medicine formula, SYP, enhances the therapeutic efficacy of anti-PD-1 in lung cancer. By regulating the gut microbiota and subsequently alleviating endoplasmic reticulum stress, SYP potentiates the host’s anti-tumor immunity. These findings provide a strong theoretical basis for the clinical application of SYP as an adjunctive therapy to overcome resistance and improve the effectiveness of anti-PD-1 immunotherapy.

Graphical Abstract