LC is the most common malignancy and the leading cause of cancer-related mortality worldwide, ranking among the cancers with the lowest survival rates (1). In recent years, both the incidence and mortality of LC have continued to rise globally (2). In 2022, ~2.5 million new LC cases and over 1.8 million deaths were reported worldwide. Epidemiological data indicate that LC has the highest incidence and mortality rates among men, and ranks second only to breast cancer among women (3). Histopathologically, LC is classified into two major types: Small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter accounting for approximately 80–85% of all LC cases (4). The development of LC is closely associated with environmental factors and genetic alterations, among which cigarette smoking remains the most recognized risk factor (5). Current therapeutic strategies for LC include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, the toxic side effects of chemotherapeutic agents and the emergence of resistance to targeted therapies and immunotherapies continue to contribute to poor prognosis and low long-term survival rates among patients with LC (6,7). Therefore, exploring novel therapeutic agents and strategies is of great clinical significance to improve the prognosis of patients with LC (8–11).

Natural compounds derived from plants possess extensive pharmacological potential and have traditionally been used to treat various diseases, including cancer. Tanshinones are natural terpenoid compounds and the major bioactive constituents isolated from Salvia miltiorrhiza, a traditional Chinese medicine widely applied in the treatment of cardiovascular and cerebrovascular diseases (12,13). Based on their structural differences, tanshinones can be classified into several types, among which tanshinone IIA (Tan IIA), dihydrotanshinone (DT), tanshinone I (Tan I), and cryptotanshinone (CPT) are considered the most representative and biologically significant (14,15). Modern pharmacological studies have demonstrated that tanshinones exhibit antiangiogenic (16), antioxidant (17), antibacterial (18), and anti-inflammatory (19) activities. Moreover, tanshinones have shown notable antitumor potential in a variety of malignancies, including gastric (20), hepatic (21), breast (22), and colorectal cancers (23), by modulating diverse cellular processes such as proliferation, invasion, metastasis, and angiogenesis. In the context of LC, tanshinones also exert significant therapeutic effects. However, the underlying molecular mechanisms remain insufficiently elucidated, and challenges such as potential drug resistance and recurrence in clinical applications need to be further addressed.

Therefore, the present review provides a systematic overview of the pharmacological mechanisms of tanshinones in LC treatment, aiming to offer a comprehensive theoretical basis and novel perspectives for optimizing tanshinone-based therapeutic strategies and promoting their translational potential in LC management (Fig. 1).

Miltiorrhizae Radix et Rhizoma (commonly known as Danshen) is derived from the dried roots of Salvia miltiorrhiza. To date, >100 chemical constituents have been isolated and structurally identified from Salvia miltiorrhiza (24). The major active components of Danshen are generally categorized into two groups: Water-soluble salvianolic acids and lipid-soluble tanshinones.

The lipid-soluble constituents mainly include Tan I (C₁₈H₁₂O₃), Tan IIA, (C₁₉H₁₈O₃), DT, CPT, isotan I, isotan IIA, and isocryptotanshinone. The water-soluble constituents comprise salvianolic acid A, salvianolic acid B, salvianolic acid C, rosmarinic acid, protocatechuic acid, and danshensu, among others (14) (Fig. 2).

Among these, the lipid-soluble tanshinones have attracted particular attention due to their high efficacy (25), low toxicity (26), favorable safety profile (27), and diverse pharmacological properties, including anticancer (28), antibacterial (29), antioxidant (30), anti-inflammatory (31), vasodilatory (32), antithrombotic (33), anti-atherosclerotic (34), neuroprotective (35), microcirculation-improving (36), anti-pulmonary fibrosis (37), and immunomodulatory effects (38). In recent years, the lipophilic components of tanshinones have been demonstrated to exhibit potent anticancer activities in LC cells.

With the increasing clinical application of tanshinones, extraction and isolation technologies have evolved considerably. These processes primarily focus on the separation of lipid-soluble diterpene quinones and water-soluble polyphenolic acids. Extraction of the lipophilic diterpene quinones mainly employs methods such as ethanol extraction, ultrasonic extraction, supercritical CO₂ fluid extraction (SFE), microwave-assisted extraction (MAE), pressurized liquid extraction, and high-speed counter-current chromatography (39). Because terpenoid compounds typically possess low polarity, chloroform, ethyl acetate, or petroleum ether are commonly used as initial extraction solvents. For compounds with slightly higher polarity, the roots are often defatted before extraction with polar solvents or mixed chloroform-methanol solutions in various ratios (14).

Modern extraction technologies optimize efficiency through physical enhancement techniques, effectively overcoming the limitations of traditional methods such as time consumption, excessive solvent use, and degradation of active components. Compared with conventional methanol extraction, SFE provides higher yield and recovery, making it particularly suitable for isolating lipophilic tanshinones (40). Both ultrasonic-assisted extraction and MAE can be performed at room temperature, avoiding the degradation of thermolabile compounds. These techniques offer several advantages, including minimal sample requirement, short extraction time, high efficiency, and reduced thermal loss (41,42).

Pharmaceutical properties of tanshinones, including their stability, toxicological safety, and metabolic behavior, have also attracted considerable attention. In general, tanshinones exhibit limited stability in aqueous solutions, a property closely associated with their chemical structure. Specifically, the quinone moiety in tanshinones confers redox-cycling activity, making them prone to structural transformation and reactions with other substances (43). As a representative diterpene phenanthrenequinone compound, Tan IIA is particularly sensitive to temperature, light, and pH conditions, and readily undergoes degradation under harsh environments such as high temperature, strong light, and extreme pH; notably, its stability can be markedly improved after encapsulation in nanocarriers (44). Toxicological research has shown that tanshinones carry a markedly low overall safety risk, with no evident acute toxicity, cytotoxicity, or genotoxicity, as demonstrated by methyl thiazolyl tetrazolium cytotoxicity assays and hypoxanthine-guanine phosphoribosyltransferase genotoxicity tests (43). Regarding in vivo metabolism, Tan IIA is preferentially distributed to the reticuloendothelial system following either intravenous or oral administration, particularly to the liver and lungs (45). Existing studies indicate that tanshinones are mainly metabolized in the liver through phase I reactions, such as hydroxylation and dehydrogenation mediated by enzymes including cytochrome P450 3A4, as well as phase II pathways such as glucuronidation; notably, phase I metabolism depends on the saturation of the core scaffold and the nature of substituent groups (46,47). Owing to their poor water solubility, low membrane permeability, and susceptibility to first-pass metabolism, several delivery strategies, such as injectable emulsions, micelles, and solid lipid nanoparticles, have been developed to effectively improve their bioavailability and plasma concentration (48,49).

Drug resistance is a key cause of chemotherapy failure in LC (114). Combining traditional Chinese medicine with chemotherapeutic agents has been shown to reverse tumor resistance and enhance drug efficacy (115).

Platinum-based chemotherapy remains the mainstay of LC treatment, but its side effects and resistance limit clinical outcomes (116). Research has shown that DT enhances the antitumor activity of cisplatin (DDP) by targeting heat shock protein family D (Hsp60) member 1 (HSPD1) and inducing ROS-mediated ER stress in LC cells, upregulating the expression of p-JNK and activating the JNK pathway (11). Moreover, Liao et al (117) found that co-administration of Tan IIA with DDP enhanced chemosensitivity by downregulating the protein expression of p-PI3K and p-Akt to inhibit the PI3K/Akt signaling pathway, allowing for reduced DDP dosage while improving efficacy and reducing toxicity.

Gefitinib (Iressa), a selective EGFR inhibitor, plays a vital role in controlling cell growth, apoptosis, and angiogenesis (118). It is clinically used to treat patients with NSCLC with chemotherapy resistance, but acquired resistance remains a major challenge (119). Tan IIA was found to downregulate SREBP1 and its downstream targets, alter lipid metabolism, and reverse gefitinib resistance in EGFR-mutant NSCLC cells both in vitro and in vivo (113). Wang et al (120) further confirmed that Tan IIA enhanced gefitinib cytotoxicity in gefitinib-resistant NSCLC cells. Moreover, the combination of Tan IIA and gefitinib enhanced the sensitivity of gefitinib-resistant HCC827 cells to gefitinib by reducing the phosphorylation level of VEGFR2 and thereby inhibiting activation of the VEGFR2/Akt signaling pathway, ultimately improving the therapeutic efficacy of the combination treatment. In addition, combined molecular docking and in vitro experiments showed that Tan IIA exhibits strong binding affinity toward PIK3R1, AKT1, mammalian target of rapamycin (mTOR), and MMP7, with binding free energies of −8.1, −12.3, −9.3, and −8.8 kcal/mol, respectively. Tan IIA was shown to form stable hydrogen bonds with key amino acid residues in these proteins, thereby inhibiting PI3K-AKT-mTOR signaling, downregulating downstream MMP7 expression, and directly suppressing MMP7 activity, ultimately inhibiting the proliferation of paclitaxel-resistant NSCLC A549/Tax cells (121). Huang et al (57) further reported that ATA binds to the ATP-binding pocket of p70S6K, thereby preventing its phosphorylation while simultaneously promoting its ubiquitin-mediated degradation. This was shown to lead to reduced synthesis of p70S6K-dependent cell cycle-related proteins, such as AURKA, downregulation of EGFR and MET expression, and concomitant upregulation of p53 and p21, ultimately inducing G₁/S cell-cycle arrest. Consequently, tanshinones have been demonstrated to effectively block protein synthesis and proliferative signaling pathways, thereby reversing drug resistance (Fig. 7).

The therapeutic potential of tanshinones in oncology has attracted considerable attention and remains a major focus of current research. A growing body of preclinical studies and experimental models has demonstrated that tanshinones can effectively inhibit tumor growth, induce cancer cell apoptosis, and modulate multiple signaling pathways involved in cancer progression. Among these, the PI3K/Akt/mTOR signaling pathway, mitochondria-dependent apoptotic pathway, VEGF/VEGFR-mediated angiogenic pathway, and key molecular regulators such as AURKA and p53 represent shared core targets through which tanshinones and their derivatives exert broad-spectrum antitumor effects in LC as well as in other malignancies, including liver, breast, and colorectal cancers. Pan-cancer mechanistic studies have shown that tanshinones can block cell-cycle progression and induce apoptosis by downregulating the PI3K/Akt/mTOR pathway (56,122,123); activate mitochondria-dependent apoptosis by modulating the Bcl-2/Bax ratio (124–126); inhibit tumor angiogenesis by suppressing VEGF/VEGFR2 signaling (16,96); and simultaneously target AURKA (61,127,128) and activate the p53 pathway (71,128,129), thereby coordinately promoting tumor cell apoptosis and reversing chemoresistance. These common molecular mechanisms provide a strong mechanistic basis for the cross-cancer antitumor application of tanshinones.

LC remains one of the most lethal malignancies worldwide. Owing to its high invasiveness, marked drug resistance, and highly complex tumor microenvironment, its clinical management is considerably more challenging than that of other solid tumors such as gastric, breast, and colorectal cancers, and its prognosis is similarly poor to that of liver cancer. In view of these pathological characteristics, the regulatory effects of tanshinones in LC appear to place greater emphasis on improving the tumor microenvironment. In terms of inflammatory regulation, tanshinones can maintain intestinal mucosal integrity, reduce LPS levels in the lung tumor microenvironment, suppress activation of the TLR4/NF-κB inflammatory signaling pathway, and thereby modulate the gut-lung inflammatory axis; to date, clear evidence for this specific mechanism has not been reported in other cancers such as gastric or liver cancer (102). At the immune level, Tan IIA can upregulate key ligands such as ULBP1 and DR5, directly acting on core signaling axes involved in NK cell recognition and killing of tumor cells, thereby enhancing the susceptibility of NSCLC cells to NK cell-mediated lysis and establishing a LC-specific mode of immune microenvironment intervention (105). By contrast, the anticancer effects of tanshinones in other malignancies may differ substantially according to the distinct pathological features of each cancer type. Taken together, tanshinones possess broad-spectrum antitumor potential. Their shared pan-cancer mechanisms provide the basis for cross-cancer application, whereas their LC-specific regulatory effects on inflammation and immunity differ markedly from the more common pathway-dependent modes of action observed in other malignancies. These distinctive features may offer novel directions and a stronger rationale for the targeted treatment of LC.

LC remains a major global health challenge accompanied by a heavy disease burden and severe clinical therapeutic dilemmas (130,131). Tanshinones exert significant antitumor effects against LC through multiple mechanisms, playing an important role in its treatment (Table I). They can block the cell cycle and regulate miRNA expression to suppress LC cell proliferation and viability, primarily by modulating diverse molecular pathways such as inhibition of the PI3K/Akt/mTOR signaling cascade and upregulation of miR-137. Moreover, tanshinones attenuate LC cell invasion and migration by regulating EMT, VEGF, and related signaling pathways, including ERK/Smad2 and EGF/VEGFR.

In addition, tanshinones have been shown to overcome immune escape, the major bottleneck in cancer immunotherapy, by modulating PD-L1 expression, activating NK cells, and remodeling the tumor immune microenvironment. Suppression of apoptosis and downregulation of tumor suppressors are major contributors to LC chemoresistance. As natural bioactive compounds, tanshinones can effectively reverse chemotherapy resistance when used in combination with conventional agents. Collectively, these findings highlight the notable potential of tanshinones as promising therapeutic candidates for LC.

However, the clinical application of tanshinones remains limited due to their poor water solubility, low bioavailability, and potential drug resistance. The development and application of nanodrug delivery systems offer a promising strategy to overcome these challenges by improving the pharmacokinetic profiles of tanshinones, enabling targeted delivery, reducing resistance, and significantly enhancing therapeutic efficacy. Common nanoparticle formulations include liposomes, polymeric nanoparticles, dendrimers, nanoemulsions, micelles, and solid lipid nanoparticles (132). For instance, Lee et al (133) developed a tanshinone nanoemulsion that exhibited superior stability, enhanced permeability, and efficient tumor-site accumulation, thereby markedly improving its inhibitory effect on LC cell proliferation and growth. The multifunctionality and high efficiency of such delivery systems provide novel opportunities for LC treatment.

Despite these advances, several challenges remain to be addressed before tanshinones can be widely applied in clinical settings. Conventional extraction methods are insufficient to meet the demand for large-scale, high-purity production, while modern directional extraction and heterologous biosynthesis technologies are still at an early stage of development. Moreover, the extremely low aqueous solubility of tanshinones results in poor bioavailability and a short half-life, severely restricting their therapeutic potential. Clinical validation also lags behind preclinical progress, as most available studies are limited in quantity and quality, making it difficult to fully assess safety and efficacy. In addition, research on tanshinone-loaded nanoparticles and other nanocarriers remains limited, and large-scale industrial production continues to face technical challenges. Finally, although short-term combination therapies have shown no major adverse effects, the long-term safety profiles, optimal dosage ratios, and potential risks of such regimens require further investigation.

In summary, current evidence indicates that tanshinones hold great promise for the treatment of LC, although several challenges must be addressed before clinical translation. Future research should focus on elucidating the core regulatory networks underlying the multi-target actions of tanshinones, optimizing their pharmacokinetic properties through advanced delivery technologies, and integrating these insights into rational clinical trial design. Such efforts will provide novel perspectives for the development of tanshinone-based targeted formulations and their clinical applications in LC therapy.