Lung cancer remains one of the most prevalent malignancies globally. Epidemiological investigations indicate that it ranks first among the eight major cancers in terms of new cases, accounting for 12.4% of all cancer cases worldwide. Furthermore, it represents the most frequently diagnosed cancer among male populations (Bray et al., 2024). Epidemiological studies have identified tobacco smoking as the primary risk factor for lung cancer pathogenesis, with additional contributions from environmental and occupational exposures, chronic pulmonary diseases, pulmonary infections, and lifestyle factors (Bade and Dela Cruz, 2020). Lung cancer is histologically classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC comprising approximately 85%–90% of all diagnosed cases (Ernani et al., 2017). For patients with early-stage NSCLC, surgical resection represents the optimal therapeutic approach (Hoy et al., 2019). However, for the majority of patients with advanced NSCLC, chemotherapy, immune checkpoint inhibitors, and targeted therapies constitute the mainstay of treatment (Li et al., 2023). The most frequently employed therapeutic regimens include PEB (cisplatin, etoposide, bleomycin), carboplatin monotherapy (AUC 7), PEI (cisplatin, etoposide, ifosfamide), TIP (cisplatin, ifosfamide, paclitaxel), and GOP (gemcitabine, oxaliplatin, paclitaxel). However, these treatment modalities are frequently associated with significant toxicities, including anemia, neutropenia, nausea, vomiting, and diarrhea (Zraik and Heß-Busch, 2021). These treatment-related toxicities not only exacerbate patients’ pain but also contribute to depression and other psychological and social distress. Furthermore, they can compromise the immune system of NSCLC patients and significantly impair their quality of life (De Ruysscher et al., 2020). Therefore, enhancing immune function is crucial for prolonging survival and improving quality of life in patients with advanced NSCLC.

The most basic theory of TCM in the treatment of NSCLC is regulating the imbalance by “strengthening the body” and “eliminating evil” when the body’s immunity is too weak and the tumor growth ability is too strong. “Strengthening the body” means enhancing the body’s anti-cancer immunity, while “ eliminating evil ” directly inhibits tumor cell growth, proliferation, invasion, and migration (Li et al., 2021).

Integrated Chinese-Western medicine therapy has demonstrated promising outcomes in the management of NSCLC. This approach enhances sensitivity to chemotherapy and radiotherapy while reducing treatment-related adverse effects, including myelosuppression, nausea, and vomiting, as well as other associated complications. Kang’ai Injection (KAI) is a standardized botanical drug preparation approved by the China National Medical Products Administration (NMPA; Approval Number: Z20026868) and manufactured by Changchun Baishan Pharmaceutical Co., Ltd. According to the product specification, it is composed of the following substances: Panax ginseng C.A. Mey. [Araliaceae; GINSENG RADIX ET RHIZOMA] (Renshen)、Astragalus membranaceus (Fisch.) Bunge [Fabaceae; ASTRAGALI RADIX] (Huangqi)、Sophora flavescens Aiton [Fabaceae; SOPHORAE FLAVESCENTIS RADIX] (Kushen), all plant materials were verified against the Plants of the World Online (POWO) database on 7 November 2025. The sourcing, processing, and production of KAI utilized in this research were conducted in full compliance with the Nagoya Protocol and relevant Chinese plant quarantine regulations (Greiber, 2019) ts preparation process focuses on the targeted extraction of active components and multi-step purification: In the extraction stage, differentiated protocols are adopted based on the characteristics of different raw materials. For Sophora flavescens (Kushen), 0.5% acetic acid aqueous solution is used as the solvent, and ultrasonic/heating reflux extraction is conducted at 50 °C–80 °C (1–2 h per time, repeated 2–3 times) to enrich alkaloids such as oxymatrine. For Panax ginseng (Renshen), 50%–70% ethanol aqueous solution is employed for heating reflux extraction at 80 °C–85 °C (1.5–2 h per time, repeated twice) to obtain saponins including ginsenoside Rg1 and Re. For Astragalus membranaceus (Huangqi), purified water is used at a solid-liquid ratio of 1:10–1:12 for decoction at 95 °C–100 °C (1.5–2 h per time, repeated twice) to retain saponins such as astragaloside IV. In the purification stage, macromolecular impurities like proteins and polysaccharides are first removed via ethanol precipitation with 70%–80% ethanol (standing at 4 °C for 12–24 h followed by centrifugation at 8000 rpm for 5 min). Subsequently, D101/HPD-100 type macroporous resins are used to enrich ginsenosides (from Panax ginseng) and astragalosides (from Astragalus membranaceus) through water elution for impurity removal and 50%–70% ethanol elution, while 732 type cation exchange resins are applied to purify alkaloids from Sophora flavescens. Finally, ultrafiltration with a 10 kDa ultrafiltration membrane and autoclaving at 121 °C for 15 min are performed to produce a sterile, pyrogen-free intravenous injection, ensuring a high recovery rate of target components throughout the process (Yuan et al., 2017; Jia et al., 2020). The combination of botanical drug formulations with chemotherapy has been demonstrated to reduce the toxicity associated with adjunctive chemotherapy (Wang et al., 2020). In addition to reducing the incidence of adverse reactions, the combination of KAI with platinum-based chemotherapy demonstrates enhanced clinical efficacy and possesses immunomodulatory properties within the tumor microenvironment (Li et al., 2019). Furthermore, Kang’ai injection has been utilized as an adjunctive therapy for various malignancies, demonstrating potential in suppressing hepatocellular carcinoma cell proliferation (Sun et al., 2021)、nasopharyngeal carcinoma cells (Wang et al., 2025) and colorectal cancer (Gao and Zhang, 2023) including nausea and vomiting, hepatic impairment, peripheral neurotoxicity, pyrexia, abdominal pain, alopecia, elevated bilirubin levels, and leukopenia induced by conventional therapies. Although KAI has demonstrated the ability to reduce toxic side effects and improve immune function as an adjunctive therapy for advanced NSCLC, current studies regarding its efficacy and safety in cancer treatment exhibit heterogeneity in sample size and research design. Therefore, we conducted this updated meta-analysis in accordance with the PRISMA checklist, aiming to comprehensively evaluate the efficacy and safety of KAI combined with conventional therapy in advanced NSCLC, thereby providing evidence for clinical practice.

Although chemotherapy remains the first-line treatment for advanced NSCLC, its associated toxicities and side effects significantly compromise patients’ quality of life and immune function. While emerging evidence suggests potential benefits of KAI combined with chemotherapy in treating advanced NSCLC, comprehensive analyses of immune-related parameters and mitigation of treatment-related toxicities remain insufficient. Therefore, we conducted this updated meta-analysis to provide clinical guidance for advanced NSCLC management and preliminary evidence for fundamental research.

In this study, we selected a total of 14 randomized controlled trials involving 1,214 patients according to predefined criteria. The results demonstrated that KAI combined with chemotherapy significantly improved the objective response rate and enhanced immune function—particularly by increasing the CD4⁺/CD8⁺ ratio—while reducing chemotherapy-related toxicities such as myelosuppression and gastrointestinal reactions. The immune system plays a crucial role in controlling the development and progression of malignant tumors in humans (Lechner et al., 2017). In clinical practice, peripheral blood T lymphocyte subsets and NK cells have emerged as established biomarkers for monitoring tumor development and progression, as well as predicting therapeutic efficacy and prognosis (Meng et al., 2019; Peled et al., 2019). Therefore, CD3⁺, CD4⁺, and CD8⁺ T-cell counts, CD4⁺/CD8⁺ ratio, and NK cell percentage were selected as key indicators for evaluating immune function in NSCLC patients. The results demonstrated that compared with chemotherapy alone, the KAI combination therapy group showed significantly increased percentages of CD3⁺ and CD4⁺ T-cells, CD4⁺/CD8⁺ ratio, and NK cells, while exhibiting decreased CD8⁺ T-cell percentage, collectively indicating enhanced immune function in patients. The main subtypes of peripheral blood T lymphocyte subsets are CD3⁺, CD4⁺ and CD8⁺ cells. Among these, CD3⁺ T cells represent the total T lymphocyte population and reflect the functional status of the host cellular immunity. CD4⁺ T cells primarily function by secreting a broad spectrum of cytokines to promote immune responses, thereby exerting anti-tumor effects. The CD4⁺/CD8⁺ ratio serves as a critical clinical indicator for assessing immune system homeostasis. NK cells mediate non-specific cytotoxicity against tumor cells. Relevant studies have demonstrated that levels of CD3⁺ and CD4⁺ T cells, CD4⁺/CD8⁺ ratio, and NK cell activity are significantly lower in patients with advanced lung cancer compared to healthy cohorts (Wu et al., 2022b; Wu et al., 2025). The primary function of CD8⁺ cells is to eliminate pathogen-infected cells and malignant transformed cells. However, research has revealed that two CD8⁺ T-cell subtypes—CD8⁺CD28⁺ (cytotoxic T cells, Tc) and CD8⁺CD28⁻ (suppressor T cells, Ts)—exhibit antagonistic roles in immune regulation (Song et al., 2018). This study further demonstrated that compared with the chemotherapy-alone group, KAI combined with chemotherapy significantly reduced the incidence of treatment-related toxicities, including leukopenia, myelosuppression, nausea and vomiting, and gastrointestinal reactions.

As an adjuvant chemotherapeutic agent, KAI is utilized in the treatment of primary liver cancer, lung cancer, colorectal cancer, and other malignancies. This intravenous preparation is manufactured from three botanical drugs and their extracts: Panax ginseng C.A.Mey. [Araliaceae; Ginseng Radix et Rhizoma], Astragalus membranaceus (Fisch.) Bunge [Fabaceae; Astragali Radix], and Sophora flavescens Aiton [Fabaceae; Sophorae Flavescentis Radix]. Its immunomodulatory effect is not the independent action of a single component, but rather results from the synergistic interaction of multiple targets and pathways. Ultimately, it achieves the clinical outcome of “enhancing efficacy while reducing toxicity” by remodeling the tumor immune microenvironment and balancing the functions of immune cell subsets. Research has indicated that the incorporation of Astragalus membranaceus-based botanical drugs into platinum-based chemotherapy regimens reduces the incidence of chemotherapy-derived toxicities, including neutropenia, nausea, and vomiting, when compared to platinum-based chemotherapy alone. Furthermore, it is noteworthy that syndrome differentiation-based formulations of Astragalus membranaceus have demonstrated superior efficacy compared to standardized oral preparations of the botanical drug (Wang et al., 2023). In addition to reducing the incidence of adverse reactions, the combination of KAI with platinum-based chemotherapy demonstrates enhanced clinical efficacy and exhibits immunomodulatory properties within the tumor microenvironment (Li et al., 2019). UHPLC/Q-TOF-MS analysis of KAI revealed that its primary constituents include oxymatrine, astragaloside IV, and ginsenosides, among other characteristic metabolites (Li et al., 2018; Jia et al., 2020). SGK3 has been identified as a target gene of miR-367-3p. Experimental studies have confirmed that oxymatrine significantly upregulates the expression of the tumor-suppressor miR-367-3p. Under oxymatrine regulation, the enhanced miR-367-3p expression subsequently downregulates its downstream target SGK3, thereby inhibiting tumor growth and suppressing the progression of NSCLC (Yu et al., 2020). The Epidermal Growth Factor Receptor (EGFR) plays a critical role in the tumorigenesis of NSCLC (Liao et al., 2017). Experimental studies have confirmed that oxymatrine effectively suppresses both anchorage-dependent and anchorage-independent growth in NSCLC cell lines, while demonstrating no cytotoxicity toward normal pulmonary cells. Furthermore, oxymatrine significantly inhibits the activity of wild-type EGFR, exon 19 deletion-mutant EGFR, and L858R/T790M double-mutant EGFR. The compound also induces G0/G1 phase cell cycle arrest in NSCLC cells through the EGFR-Akt signaling axis. Additionally, in vivo experiments using xenograft mouse models have validated that oxymatrine significantly inhibits tumor growth (Li et al., 2017). Research has demonstrated that ginsenoside CK enhances the anti-proliferative, pro-apoptotic, and anti-migratory effects of gefitinib in both primary and acquired drug-resistant NSCLC. This compound suppresses the expression of HIF-1α, VEGF, FGF, and MMP-2/9, while upregulating the anti-angiogenic factor PF4 and enhancing pericellular matrix formation, ultimately promoting vascular structure normalization (Song et al., 2024). Studies in murine models have revealed that ginsenoside Rh2 promotes the infiltration of CD4⁺ and CD8⁺ T lymphocytes into tumor tissues, thereby enhancing anti-tumor efficacy (Wang et al., 2017). Research has demonstrated that high-dose astragaloside IV significantly inhibits NSCLC cell proliferation, while low-dose treatments show no apparent cytotoxicity. Furthermore, the combination of astragaloside IV with cisplatin enhances chemosensitivity in NSCLC cells through suppression of B7-H3 expression at both transcriptional and protein levels (He et al., 2016). Research has further demonstrated that the combination of astragaloside IV with anti-PD-1 therapy inactivates both PI3K/Akt and ERK signaling pathways, suppresses tumor cell proliferation, and induces apoptosis. This combined treatment promotes M1 macrophage polarization and T-cell activation, resulting in significant reduction of tumor volume and weight in LLC tumor-bearing mice (Wu et al., 2024). Furthermore, studies indicate that astragaloside III enhances the anti-tumor response of natural killer (NK) cells by upregulating the expression of NKG2D and IFN-γ (Chen et al., 2019). The aforementioned components collectively regulate immune function through complementary pathways, which directly correlates with the findings in this study, namely, the increased percentages of CD3⁺ and CD4⁺ T cells and enhanced NK cell activity observed in the combination therapy group. This provides a theoretical foundation for KAI’s role in improving immune function.

The strengths of this study lie in its strict adherence to the PRISMA guidelines and the prospective registration of the study protocol on the PROSPERO platform, ensuring methodological rigor. Through systematic searches of Chinese and English databases, we included 14 randomized controlled trials with a total sample size of 1,214 patients. Data extraction and quality assessment were independently performed by two investigators with cross-verification, effectively minimizing the risk of subjective bias. Our comprehensive analysis not only evaluated clinical efficacy and core immune function parameters but also systematically assessed multiple chemotherapy-related adverse reactions. Furthermore, we validated the robustness of the primary outcomes through subgroup analyses, sensitivity analyses, and trial sequential analysis, thereby enhancing the reliability of our conclusions.

This study has several limitations. All studies included in this analysis were conducted in China, indicating a significant geographical limitation. On one hand, differences in genetic background, dietary structure, and the principles of Traditional Chinese Medicine diagnosis and treatment based on pattern differentiation between the Chinese population and those in other countries or regions may lead to racial heterogeneity in the therapeutic response to KAI. On the other hand, while the selection of chemotherapy regimens and standards for supportive care for NSCLC within the Chinese healthcare system align with international guidelines to some extent, distinct regional characteristics persist, which may influence the assessment of adverse event incidence rates. Most studies provided inadequate reporting on key methodological aspects such as random sequence generation, allocation concealment, and blinding implementation, potentially introducing performance and detection biases. The evidence for certain critical outcomes, including NK cell parameters, was limited by the small number of included studies. Furthermore, several immune indicators demonstrated substantial statistical heterogeneity; although random-effects models were employed and subgroup analyses conducted, the underlying clinical heterogeneity could not be fully elucidated. Therefore, the generalizability of the conclusions from this study requires cautious interpretation. Future research should involve multicenter, cross-regional randomized controlled trials that enroll patients of diverse ethnicities and from varying healthcare environments to further validate the efficacy and safety of KAI combined with chemotherapy.

The combination of KAI with chemotherapy for advanced non-small cell lung cancer demonstrates immunomodulatory effects by enhancing peripheral blood CD3⁺, CD4⁺, CD4⁺/CD8⁺ ratios and NK cell percentages, while reducing tumor marker levels including CEA and VEGF. This integrated approach achieves the clinical effect of “enhancing efficacy and reducing toxicity by improving objective response rates and simultaneously decreasing chemotherapy-related adverse reactions such as leukopenia, myelosuppression, nausea, and vomiting, thereby holding significant importance for patients’ quality of life. However, the strength of evidence remains constrained by methodological limitations in included studies, including generally low quality, high population homogeneity, and absence of long-term survival data. Future investigations should prioritize multicenter, large-sample, double-blind randomized controlled trials to optimize KAI dosage regimens and treatment duration, while further validating its long-term efficacy and applicability across diverse ethnic populations, thereby providing higher-level evidence for its standardized application in advanced NSCLC treatment.