Globally, lung cancer remains the leading cause of cancer-related deaths (Leiter et al., 2023). Although considerable advances have been made in its treatment, including surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, and cellular therapies (Lee et al., 2023; Riely et al., 2024), challenges persist in the management of advanced lung cancer (Lee et al., 2023; Riely et al., 2024). Consequently, various complementary and alternative medicine therapies, including traditional herbal medicines, are increasingly being used not only to alleviate cancer-associated symptoms but also to enhance the efficacy of standard treatments and reduce adverse effects, with growing interest and supporting evidence (Guerra-Martin et al., 2021; Li et al., 2021).

Yukgunja-tang (YGJT, also known as Liujunzi Decoction in Chinese and Rikkunshito in Japanese) is a widely used herbal formula in Asia for improving gastrointestinal symptoms, including functional dyspepsia. YGJT was first documented in 1345 during the Yuan dynasty in the classical medical text Shi Yi De Xiao Fang (Efficacious Remedies of Physicians), authored by Yilin (2009). It comprises six primary medicinal herbs: Ginseng Radix et Rhizoma (Panax ginseng C.A.Mey.), Atractylodis macrocephalae Rhizoma (Atractylodes macrocephala Koidz.), Poria (Macrohyporia cocos (Schwein.) I.Johans. & Ryvarden), Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch. ex DC.), Pinelliae Rhizoma (Pinellia ternata (Thunb.) Makino), and Citri Reticulatae Pericarpium (Citrus reticulata Blanco) (Inokuchi et al., 2021). In traditional East Asian medicine, YGJT is believed to tonify qi, strengthen the spleen, and eliminate dampness, primarily for treating spleen and stomach qi deficiency accompanied by dampness (Wu et al., 2022). This pattern presents with symptoms such as dyspepsia, fatigue, and weakness, which frequently occur in individuals receiving conventional cancer treatments.

In traditional East Asian medicine, the principle of reinforcing healthy qi to eliminate pathogenic factors constitutes a core therapeutic rationale in the management of cancer (Liu et al., 2018). Lung cancer is defined as a pattern of qi deficiency of the spleen and lung with concomitant phlegm-damp accumulation and secondary impairment of spleen function (You, 2016). Therapeutic strategies focus on strengthening the spleen, supplementing qi, transforming phlegm, and eliminating stasis, and also address chemotherapy-induced impairment of vital qi and gastrointestinal function by reinforcing healthy qi and restoring spleen-stomach integrity (Zhou et al., 2015).

YGJT and its modified formulations are widely prescribed during cancer treatment in East Asian countries (Iwase et al., 2012; Li et al., 2018). A systematic review published in 2023 identified YGJT as the most frequently used herbal intervention for cancer-related anorexia, reflecting its traditional indication for spleen-stomach deficiency and its capacity to address qi deficiency (Park et al., 2023). Moreover, in patients with lung cancer, the adjunctive use of YGJT alongside standard therapies has been associated with improved prognosis, delayed disease progression, and prolonged survival (Liu et al., 2020; Xi et al., 2025). These clinical benefits are consistent with traditional medical theory, which attributes lung cancer to qi deficiency of the spleen and lung and recommends reinforcing qi and resolving phlegm (Li et al., 2017). Through this mechanism, YGJT supports its role as an effective adjunct to standard therapy in lung cancer management.

Although several systematic reviews of randomized controlled trials (RCTs) have examined the efficacy of YGJT and its modified formulations in gastrointestinal disorders, no review has specifically focused on its role in lung cancer (Ko et al., 2021; Sun et al., 2024; Wang et al., 2024). In lung cancer management, YGJT may alleviate cancer- and chemotherapy-related symptoms and improve the effectiveness of anticancer therapies. Therefore, a systematic evaluation of its efficacy and safety is warranted to guide its appropriate integration into clinical practice. This review aims to assess the efficacy and safety of YGJT as an adjunct therapy for individuals with lung cancer and to provide evidence supporting its clinical use.

This systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42024619038) to ensure transparency and alignment with established review standards. No amendments have been made since registration. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021), the PRISMA extension for Chinese Herbal Medicines 2020 (Zhang et al., 2020), and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al., 2024) to maintain methodological rigor. The PRISMA Checklist is provided in Supplementary Table S1.

This systematic review included 31 RCTs with 2,496 participants who met the inclusion criteria. Modified YGJT combined with antitumor therapy improved both ORR and DCR compared to antitumor therapy alone. Furthermore, YGJT significantly enhanced patients’ quality of life and immune function, while reducing tumor markers and treatment-related adverse events.

Lung cancer has the highest incidence and mortality of all cancers worldwide, with an estimated annual incidence of 2.48 million cases and 1.82 million deaths (Bray et al., 2024). Significant advancements have been made in standard treatment modalities, surgery, chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibition, along with recent progress in nano-drug delivery systems, molecular targeted therapies, photothermal approaches, and immunotherapy, all contributing to incremental improvements in survival rates (Thai et al., 2021; Li et al., 2023). Nevertheless, the 5-year survival rate remains alarmingly low, highlighting persistent challenges in disease management (Li et al., 2023). As a result, the therapeutic potential of traditional herbal medicine is increasingly recognized as a promising complementary strategy to enhance efficacy and alleviate patient burden.

In traditional East Asian medicine, the pathology of lung cancer is attributed to root deficiency with excess tip, where an underlying Qi deficiency in the spleen and lung leads to the formation of byproducts, such as blood stasis or phlegm dampness (Liu et al., 2018). This imbalance is often exacerbated during anti-tumor therapy, as patients frequently experience physical weakness manifesting as symptoms of Qi deficiency and phlegm dampness, including nausea, vomiting, fatigue, and malaise. These symptoms ultimately reduce treatment adherence and patient quality of life. To address these issues, traditional East Asian medicine applies the primary principles of “strengthening the body” and “eliminating evil,” which refer to enhancing immune defenses against tumors and inhibiting tumor growth, proliferation, and metastasis in terms of Western medicine (Li et al., 2021).

YGJT is a representative prescription for the treatment of spleen Qi deficiency and phlegm dampness. YGJT exerts effects such as tonifying the spleen and lung, benefiting Qi and nourishing blood, and expelling dampness: Ginseng Radix et Rhizoma strengthens the spleen and benefits the lung, replenishes Yuan-primordial Qi, nourishes blood, and generates fluids; Poria strengthens the spleen, calms the mind, and drains dampness; Atractylodis Macrocephalae Rhizoma tonifies the spleen and benefits the lung, dries dampness, and promotes urination; Citri Reticulatae Pericarpium harmonizes the middle jiao, circulates Qi, disperses nodules, and dries dampness; Pinelliae Rhizoma downregulates Qi, resolves masses, transforms phlegm, and dries dampness; and Glycyrrhizae Radix et Rhizoma tonifies the spleen, nourishes blood, and coordinates medicines (Nie et al., 2022).

Originally recorded in the classical text Shi Yi De Xiao Fang (Efficacious Remedies of the Physicians) as a prescription for treating symptoms such as loss of appetite, vomiting, diarrhea, and indigestion, YGJT has since been widely used for gastrointestinal disorders (Yilin, 2009). Building on this traditional application, it has been investigated for its potential in lung cancer to manage gastrointestinal symptoms caused by the disease itself and by anticancer treatments (Wu et al., 2022). Both preclinical and clinical studies have reported that YGJT increases appetite, protects gastric mucosa, and promotes digestive fluid secretion, thereby addressing appetite loss in individuals with cancer (Sun et al., 2020; Dai et al., 2022; Wu et al., 2022). YGJT prevents anorexia and gastrointestinal dysmotility by antagonizing 5-HT2b/2c receptors in the stomach and hypothalamus, activating the ghrelin receptor GHS-R1a, and inhibiting deacylating enzymes to enhance ghrelin activity (Fujitsuka and Uezono, 2014; Yamada et al., 2021). Additionally, YGJT has demonstrated efficacy in the gastrointestinal system by improving stress-induced gastric hypersensitivity through NO-mediated pathways, promoting gastric accommodation, reducing gastric dysmotility, and inhibiting adrenocorticotropic hormone and cortisol (Inokuchi et al., 2021). In particular, its mechanisms in cancer-induced and chemotherapy-induced anorexia involve activation of ghrelin signaling pathways, antagonism of 5-HT2B/2C receptors, and protection of the gastrointestinal mucosal barrier (Wu et al., 2022; Sun et al., 2024). Through these mechanisms, YGJT has been shown in animal and clinical studies to prevent cancer cachexia and increase food intake following chemotherapy (Fujitsuka and Uezono, 2014; Yamada et al., 2021). This anti-cachectic effect is of high translational value, as cancer-associated cachexia is a major contributor to morbidity and mortality in lung cancer. By improving nutritional status, YGJT may help break the cycle of weight loss and functional decline that limits patients’ tolerance to aggressive anticancer therapies. Previous systematic reviews and meta-analyses have primarily examined the effects of YGJT on upper gastrointestinal symptoms, such as functional dyspepsia and chemotherapy-induced anorexia (Mogami and Hattori, 2014; Hoshino et al., 2019; Ko et al., 2021; Sun et al., 2024; Wang et al., 2024). These findings align with the present study, which demonstrated a reduction in digestive tract reactions, further supporting the effectiveness of YGJT in managing gastrointestinal symptoms in lung cancer treatment.

In the subgroup analysis, JCYGJT exhibited greater efficacy against digestive tract reactions than modified YGJT or HSYGJT. This could be explained by its focus on benefiting Qi and strengthening the spleen through the increased proportion of Atractylodis Macrocephalae Rhizoma as a primary component, combined with the addition of Aurantii Fructus, which regulates Qi and transforms phlegm, and Aucklandiae Radix, which regulates Qi and resolves masses (Bi et al., 2024). These combined effects likely enhanced its digestive properties, enabling better management of gastrointestinal side effects. However, the small number of available studies makes it difficult to draw definitive conclusions about the relative superiority of these formulations. As the synergistic use of herbs is a fundamental principle of traditional East Asian medicine (Wang et al., 2012), further research is needed to better differentiate the effects of YGJT and its modified decoctions and assess their clinical implications.

This study indicates that YGJT may also enhance the effectiveness of antitumor therapy, an area that has been relatively underexplored. This effect is reflected in the observed improvements in ORR and DCR. From a clinical standpoint, the magnitude of this synergy is meaningful. Applying our pooled risk ratio of 1.69 to the baseline control group response rate of 31.1% yields an absolute improvement in ORR of approximately 21.5%. This level of benefit is noteworthy, as more modest improvements in ORR have been considered clinically significant in pivotal lung cancer trials (Cho et al., 2022). There is substantial evidence from preclinical studies that YGJT has antitumor effects. For example, YGJT has been reported to exert antitumor effects in esophageal squamous cell carcinoma by inhibiting the miR-34a/STAT3/IL-6R pathway and enhancing antitumor immune responses by inhibiting PD-1, thereby restoring T-cell cytotoxicity (Han et al., 2023). In liver cancer, YGJT was observed to downregulate UBE2I and the NF-κB/PD-L1 pathway via miR-122-3p (Guo et al., 2024). In NSCLC, YGJT has been suggested to modulate several genes associated with neutrophils in ways that enhance immune responses or mitigate inflammatory side effects, with RNA-induced gene silencing potentially contributing to its anticancer effects (Chen et al., 2017; Xin et al., 2022).

From the perspective of traditional East Asian medicine, the principle of “strengthening the body” and “eliminating evil” suggests that YGJT could potentiate cancer treatment by tonifying Qi, mitigating pathological byproducts such as phlegm dampness, and directly contributing to tumor suppression. Sensitivity analysis using Qi deficiency-related patterns as diagnostic criteria showed improved ORR while reducing the occurrence of adverse events, supporting the clinical relevance of these principles. However, the results for other outcomes were inconsistent, likely because most studies using pattern identification were conducted on advanced lung cancer cases, and the limited number of studies reduced statistical power. Future studies using pattern identification could facilitate robust comparisons between patterns and clarify those most suitable for YGJT in lung cancer treatment.

Furthermore, YGJT resulted in a higher tumor response rate when combined with chemotherapy than when combined with EGFR-TKIs. Although this suggests that YGJT enhances the cytotoxic effects of conventional agents, it is more likely attributable to the more advanced cancer stage in the EGFR-TKI group, possibly related to the indication criteria for EGFR-TKI use. Additional studies examining possible synergistic or antagonistic interactions between YGJT and other Western therapies, such as immunotherapy and radiotherapy, which remain largely unexplored, are warranted. Such research is essential to validate YGJT as a viable adjunct to standard oncological treatments.

A key effect of YGJT in cancer treatment may be its immunomodulatory activity. The role of lymphocyte subsets in cancer prognosis remains incompletely understood, with studies reporting varied results. While CD4⁺ T cells enhance immune responses, CD8⁺ T cells can suppress immune activity and are associated with tumor progression and growth (Wang et al., 2013). CD4⁺ T cells are believed to play a critical role in anti-tumor immunity by directly killing cancer cells, with decreased CD4⁺ levels linked to lower survival rates in patients with lung cancer (Oh and Fong, 2021; Eberst et al., 2022; Malyshkina et al., 2023). The CD4+/CD8+ ratio reflects immune function balance and is an important prognostic biomarker for assessing immune competence in patients with cancer (Xu et al., 2018). Additionally, patients with NSCLC who respond well to anti-PD-1 treatment show increased levels of CD4⁺ T cells and a higher CD4+/CD8+ ratio (Zhuang et al., 2024). Our analysis aligns with these principles, revealing that YGJT significantly increased total T cells (CD3⁺) and CD4⁺ T cells, leading to an elevated CD4+/CD8+ ratio. These findings suggest that YGJT enhances systemic immune function. This enhancement is of high translational value, as it suggests YGJT may counteract the profound T-cell exhaustion and immunosuppressive tumor microenvironment that are key features of lung cancer pathophysiology, potentially restoring the patient’s capacity to respond to both conventional and immune-based therapies.

The decrease in CD8⁺ cell levels observed in this study is controversial, as research on its prognostic significance in lung cancer remains inconclusive. Some studies have indicated that an increase in CD8⁺ T cells is an independent prognostic factor for poor survival in patients with malignant mesothelioma or advanced NSCLC (McCoy et al., 2013), while a systematic review reported that CD3⁺, CD4⁺, and CD8⁺ cells are all positively associated with improved overall survival in patients with NSCLC (Yan et al., 2024). These results suggest that while YGJT may boost immune function and demonstrate anticancer efficacy, the changes in CD8⁺ levels and their effects on prognosis require further investigation through clinical trials.

Tumor markers are closely associated with the disease stage of lung cancer and are widely used for screening, clinical diagnosis, and prognostic assessment (Kumar et al., 2006; Arya and Bhansali, 2011). Specifically, CEA, NSE, SCC, CYFRA 21-1, and CA19-9 have become established indicators for evaluating prognosis in lung cancer, with reductions in these markers often correlating with extended survival (Holdenrieder et al., 2017; Yang et al., 2019; Trulson and Holdenrieder, 2024). In this study, YGJT was shown to reduce these tumor markers. However, due to the high heterogeneity of the included studies, relatively small sample sizes, and lack of data on combination therapy with EGFR-TKIs, further research is required to elucidate the relationship between YGJT and tumor markers.

KPS is one of the most critical prognostic factors affecting the outcomes of patients with cancer, including those with lung cancer (Buccheri et al., 1996; West and Jin, 2015). Therefore, maintaining a high KPS score is crucial in lung cancer treatment. Adding YGJT to conventional therapy resulted in relatively greater improvements in both KPS and symptom scores, suggesting that YGJT not only synergizes with antitumor treatments but also improves patient symptoms, enhances quality of life, and increases treatment tolerability, thereby supporting the overall goals of cancer therapy. The ability of adjunctive YGJT to significantly improve KPS suggests its benefits translate to a tangible enhancement in patients’ functional status and daily life. The mean improvement of 8.62 points observed in our analysis substantially exceeds the 3.83-point threshold empirically identified as the minimal clinically important difference for a noticeable improvement in KPS (Ringash et al., 2007). This indicates that the observed change is not only statistically significant but also represents a highly meaningful clinical benefit for patients.

Another major aspect of the therapeutic effects of YGJT is its reduction of adverse effects associated with cancer treatment. These adverse effects, primarily bone marrow suppression and gastrointestinal toxicity, often lead to a decline in quality of life. YGJT effectively reduced these side effects while improving patients’ quality of life. YGJT’s ability to mitigate a spectrum of adverse events, including both myelosuppression and gastrointestinal toxicity, contrasts with standard supportive care, which often requires the administration of multiple single-target agents. This suggests a potential role for YGJT as a broad-spectrum supportive care intervention, capable of simplifying patient management. In vivo studies have reported that YGJT and its modified formulations prevent cisplatin-induced neurotoxicity through antioxidant effects, regulation of mitochondrial function, and alleviation of paclitaxel-induced neuropathy and leukopenia (Chiou et al., 2018; Shiah et al., 2023). Consistent with its immune-balancing properties, YGJT also reduced myelosuppression and leukopenia in this study, suggesting an improvement in immune function that contributes to its anti-tumor effects. Further research on the immunomodulatory effects of YGJT may provide stronger evidence of its potential synergistic effects with current anticancer agents.

The strengths of this study are as follows: To our knowledge, this is the first meta-analysis examining the synergistic effects of YGJT and antitumor therapy in lung cancer patients. This review encompasses a broad range of outcomes, including ORR, DCR, KPS score, clinical symptom score, immune function markers, tumor markers, and treatment-related adverse events, providing a comprehensive assessment of the efficacy and safety of YGJT. This study used a robust data extraction process conducted by multiple independent reviewers to ensure high reliability and minimize bias. Sensitivity analyses specific to advanced-stage lung cancer further reinforced the robustness of the results, while publication bias assessments using funnel plots and Egger’s test added an additional layer of validation. We also conducted an extensive database search without restrictions on language, publication year, or publication type.

Despite its strengths, this review has several limitations. First, a primary limitation of this review is the inability to perform our pre-specified comparative subgroup analyses, particularly for cancer stage and histological subtype. This was due to an insufficient number of included studies representing certain key subgroups (e.g., early-stage or SCLC), which prevented a direct meta-analytic comparison. However, as pre-specified in our protocol, we conducted a sensitivity analysis on the cohort of studies involving advanced-stage cancer, which largely confirmed the robustness of our overall findings for this population. Second, the generalizability of the findings is limited as most studies were conducted in China. This geographical concentration raises questions about the applicability of these results to other ethnic populations. Third, our search strategy, while extensive across published literature databases, did not include a specific search of clinical trial registries or other sources of grey literature. This could have resulted in the omission of relevant unpublished or ongoing trials, representing a potential source of publication bias. Additionally, the majority of the included RCTs were rated as having a “high” or “some concerns” for risk of bias, primarily due to inadequate blinding and unclear randomization methods. This high risk of bias substantially tempers confidence in the observed effect sizes and may have led to an overestimation of the treatment benefit. Furthermore, the substantial clinical heterogeneity, driven by the wide variability in modified YGJT interventions, complicates the attribution of the observed effects to a single, standardized intervention. Future research should aim to address these limitations by including high-quality multicenter RCTs with detailed protocols to validate the findings and explore the application of YGJT in broader, more diverse populations.

This systematic review provides evidence supporting the efficacy and safety of modified YGJT as an adjuvant therapy for lung cancer. The findings indicate that YGJT improves ORR and DCR, enhances KPS scores and clinical symptoms, boosts immune function, and reduces tumor markers and treatment-related adverse events. Despite these promising results, the overall quality of the included studies was low, with limitations such as small sample sizes, potential biases, and high heterogeneity. These challenges underscore the need for well-designed, large-scale, multicenter RCTs to confirm these findings and further investigate the underlying mechanisms of the effects of YGJT. Future research should aim to address these limitations and explore the interactions between YGJT and contemporary cancer treatments, including immunotherapy and radiotherapy, to fully unlock its potential in comprehensive cancer care.