Angiogenesis is a critical driver of lung cancer cell growth, invasion, and metastasis, with VEGF serving as a key mediator in this process. In NSCLC, elevated levels of angiogenic markers, including VEGF, correlate with poorer prognoses (27), underscoring VEGF’s central role in tumor neovascularization (28). The VEGF family, comprising VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), exhibits specific functions within various tissues. VEGF-A, the most potent angiogenic factor, is essential for regulating endothelial cell sprouting, mitogenesis, migration, vasodilation, and vascular permeability (29, 30). In the heart, VEGF-B supports neuronal survival and cardiovascular growth through angiogenesis. It regulates cardiac angiogenesis and sympathetic innervation by inducing tissue-specific angiogenic responses in the myocardium, upregulating nerve ciliary protein (Nrp-1) expression, and mediating VEGFR-1 and Nrp-1 to promote nerve growth and protection. This mechanism contributes to alleviating ischemic heart disease (31), thereby aiding ischemic heart disease recovery (32). VEGF-C and VEGF-D facilitate tumor growth and metastasis through VEGFR-3-mediated lymphangiogenesis and lymphatic metastasis (33). Upon binding to its receptor, VEGF activates downstream signaling pathways such as MAPK/ERK, PI3K/AKT, PKC, and FAK, which collectively support angiogenesis. Although VEGF/VEGFR is not the sole regulatory axis, it plays an indispensable role in angiogenic signaling (34). Consequently, antivascular drugs targeting VEGF or VEGFR have emerged as promising therapeutic options, primarily including monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKIs), such as bevacizumab, ramucirumab, and acitretinib. Monoclonal antibodies exhibit high specificity by binding directly to VEGF or VEGFR, preventing receptor interaction and thereby exerting anti-angiogenic effects through receptor blockade. Tyrosine kinase inhibitors, conversely, bind to receptor tyrosine kinases, inhibiting their kinase activity and thus impeding downstream signaling (35, 36). Research confirms that VEGF and VEGFR are key regulators in lung cancer angiogenesis, serving as primary therapeutic targets for antivascular drug development to inhibit tumor growth, metastasis, and drug resistance. However, tumors often develop multiple drug resistance (MDR) through mechanisms such as decreased intracellular drug concentrations, altered drug targets, and imbalances in metabolic detoxification and DNA repair. Overexpression of transporter proteins in tumor cells further limits drug efficacy by blocking drug entry and actively expelling intracellular drugs. These transporters expel lipophilic chemotherapeutic agents, reducing their effective intracellular concentrations and establishing resistance (37). To counteract drug resistance, current treatments employ sequential maximal dose-density regimens to maximize cell destruction and minimize resistance onset (38). Dual targeting of the VEGF and ANG2 pathways has proven more effective than single-target approaches, enhancing antiangiogenic therapy outcomes (39). Despite progress, many molecular mechanisms underlying VEGF-targeted antivascular therapies remain to be elucidated, necessitating further investigation (40).

PDGF, a fundamental protein stored in platelet α-granules (41), along with its receptors (PDGFRα and PDGFRβ), is expressed in numerous malignant cells and tissues, including NSCLC, gastrointestinal stromal tumors (GIST), and pancreatic, breast, ovarian, hepatocellular, and neuroendocrine cancers (42). In NSCLC, overexpression of PDGFRα/β and PDGF-A/B correlates with poor prognosis; PDGF-AA, for instance, regulates VEGF expression via autocrine signaling, advancing the transformation of precancerous lesions into aggressive malignancies (43). Additionally, mutations in the PDGFR-α gene enhance PDGFRα expression, triggering ligand-independent PDGF signaling that fosters tumor growth in NSCLC (44). In GIST, PDGF ligand binding to PDGFRα and PDGFRβ activates the STAT pathway, influencing disease progression (45). In breast cancer, high PDGF-C expression correlates with lymph node metastasis, HER2 amplification, and elevated Ki-67 proliferation, driving progression via autocrine and paracrine signaling (46). In cholangiocarcinoma, hypoxia-induced PDGF-D upregulation in cholangiocarcinoma (CAA) cells activates a paracrine loop in the tumor-associated stroma, coordinating lymphangiogenesis and accelerating regional lymph node metastasis (47). PDGF activates signaling through PDGFR-mediated cellular pathways, where receptor binding initiates dimerization and phosphorylation, creating sites for downstream signaling molecule attachment and activating pathways such as PI3K/AKT, Ras/MAPK, PLC-γ, DAG, PKC, and JAK/STAT (48). Studies reveal that inhibiting the PDGF/PDGFR pathway effectively hinders tumor cell proliferation and angiogenesis (49). TKIs, which neutralize PDGFR antibodies and antagonize PDGFR kinase activity (50), have shown promise in targeted therapies, notably improving the outcomes of patients with NSCLC. Anlotinib, for example, is utilized as a third-line treatment for advanced NSCLC, targeting VEGFR to inhibit angiogenesis and lung cancer cell proliferation, demonstrating efficacy in advanced cases (51, 52). However, TKI-related toxicity and resistance present significant challenges in prolonged therapy, necessitating further in-depth research to optimize efficacy and mitigate these issues (53).

Hypoxia is often indicative of solid tumor presence, activating the HIF family to modulate gene expression in both tumor cells and immune cells within the TME, thereby influencing tumor progression and therapeutic response (54). The HIF family consists of isoforms HIF-1, HIF-2, and HIF-3, each with distinct functions and transcriptional activities (55). Among these, HIF-1 has been widely identified across various cancers and plays a pivotal role in cancer development, acting as a key transcription factor (TF) that drives cancer progression and serves as a target for therapeutic intervention. HIF-1 promotes cancer cell growth, survival, angiogenesis, metastasis, and treatment resistance (56). In the hypoxic TME, rapid tumor cell proliferation outpaces the oxygen supply from surrounding blood vessels, creating an imbalance that triggers a cellular adaptive response coordinated by HIF-1 (57). HIF-1 itself is a heterodimer of α and β subunits, with HIF-1α particularly induced under hypoxia to regulate genes related to cancer cell proliferation and angiogenesis (58). HIF-1α transcriptionally activates several pro-angiogenic molecules by binding directly to promoter regions. Specifically, HIF-1α binds to the hypoxia response element (HRE) on VEGF and VEGFR1 gene promoters, inducing VEGFA and VEGFR1 expression, which promotes tumor angiogenesis through VEGF and ANGPTL4 (59). Under hypoxic conditions, HIF-1α stabilizes and initiates the expression of multiple genes through a gene expression cascade involving the MAPK pathway and VEGF signaling (60). In this process, HIF-1α binds to the hypoxia-responsive element (HRE) within the VEGF promoter, forming an HIF-1α/HRE complex that directly upregulates VEGFR-1 expression in tumor cells. This amplification of VEGF signaling promotes both solid tumor angiogenesis and pathological angiogenesis (61). Ropivacaine, a local anesthetic, has been shown to inhibit HIF-1α signaling in lung cancer cells, along with downstream VEGF signaling, thus reducing angiogenesis in malignant lung cancers (62). Additionally, HIF-1α activation of the Hippo-YAP pathway accelerates malignant progression in NSCLC, while silencing HIF-1α induces ferroptosis and inhibits NSCLC invasion (63). These findings underscore the extensive interplay of HIF-1 signaling pathways in lung cancer development, suggesting that targeting HIF-1 could open new avenues for the development of effective HIF inhibitors and therapeutic strategies (64).

Among the various regulators of angiogenesis, basic fibroblast growth factor (FGF2) is considered the first identified pro-angiogenic molecule, promoting angiogenesis by activating FGF receptor 1 (FGFR1) signaling in endothelial cells (65). To counteract the effects of the highly expressed FGF2/FGFR1 pathway, research indicates that VEGF-B can act as a unique angiogenic factor; although it typically has limited angiogenic activity, it can inhibit tumor growth and angiogenesis under specific conditions by suppressing FGF2-induced Erk phosphorylation and thus reducing FGF2-driven angiogenesis (66, 67). This mechanism offers a potential therapeutic strategy for controlling excessive angiogenesis, contributing to targeted therapies aimed at preventing lung cancer cell metastasis and dissemination. In the context of advancing lung cancer immunotherapy research, miRNAs, a subset of non-coding RNAs, have emerged as key regulators of cancer cell growth, metastasis, angiogenesis, and apoptosis. For instance, miR-937-3p, often highly expressed in patients with lung adenocarcinoma (LUAD), activates the PI3K/AKT pathway by targeting the downstream gene SOX11, thereby enhancing NSCLC angiogenesis and facilitating metastasis (68, 69). Additionally, dietary compounds such as flavonoids, retinoids, triterpenoids, omega fatty acids, and carotenoids have demonstrated promising roles in anti-angiogenic therapy within current cancer immunotherapy approaches (70).

TGF-β is widely recognized as a central driver of cancer cell plasticity through EMT. The TGF-β family includes 33 evolutionarily conserved proteins, such as TGF-β1, TGF-β2, TGF-β3, activins, bone morphogenetic proteins (BMPs), inhibins, growth and differentiation factors (GDFs), and mullerian inhibitory substances (MISs) (74). TGF-β, particularly prominent in advanced cancers, is closely linked to metastasis and chemotherapy resistance. During EMT, TGF-β activates the SMAD pathway following ligand-induced receptor activation, where SMAD proteins transmit signals to the nucleus to regulate target gene expression (75). TGF-β signaling begins with the activation of membrane-bound type I (TGFβRI) and type II (TGFβRII) receptors, leading to SMAD2 and SMAD3 activation. These form a complex with SMAD4, translocating to the nucleus to interact with DNA-binding TFs and co-regulators, modulating gene expression (76). Additionally, the TGF-β receptor complex activates non-SMAD pathways, including RAS/MAPK, TAK1/JNK/p38MAPK/IKK, and PI3K/Akt (77) ( Figure 2 ). Given its overexpression and pro-tumorigenic effects across many tumor types, TGF-β is a promising therapeutic target. Combining TGF-β inhibitors with immune checkpoint blockade or chemotherapy can effectively reduce cancer cell plasticity (78). Neferine, a bisbenzylisoquinoline alkaloid, has been found to downregulate TGF-β in NSCLC, modulating MST1 to induce ROS formation, thereby promoting apoptosis and preventing proliferation, metastasis, and EMT (79). Additionally, TGFβ1-induced upregulation of PD-L1 in tumor cells has emerged as a novel mechanism of immunosuppression in NSCLC. Bintrafusp alfa (M7824), targeting both PD-L1 and TGF-β, has shown efficacy in inhibiting tumor mesenchymalization, reducing PD-L1-dependent immunosuppression, and overcoming chemoresistance in NSCLC (80). These studies, along with the development of more potent and specific TGF-β inhibitors, hold potential for treating tumors that thrive in TGF-β-rich environments (81).

EMT-TFs ( Table 2 ) include the zinc finger proteins SNAI1 (Snail1) and SNAI2 (Snail2, or Slug), twist-related proteins 1 and 2 (Twist1/2), and the zinc finger e-box binding homology cassette 1/2 (ZEB1/2). Upregulation of these EMT-TFs drives cancer cells to transition from a differentiated epithelial state to a stem cell-like state, enhancing metastatic potential (82). Among them, Snail1 plays a critical role, with its expression preceding other EMT-TFs. Snail1 activates additional EMT-TFs and suppresses epithelial genes like epithelial cadherin (E-cadherin), allowing tumors to adopt a mesenchymal morphology and invasive capacity (83). Snail1 also recruits chromatin-modifying enzymes to the E-cadherin promoter, promoting DNA methylation and transcriptional repression of E-cadherin, thereby driving EMT and promoting dedifferentiation of cancer cells into cancer stem cell-like (CSC) phenotypes. Snail1 expression is linked to increased invasion and metastasis across various cancer types, including lung cancer. Notably, reducing Snail1 expression has been shown to enhance the efficacy of numerous chemotherapies and immunotherapies. Although direct chemical inhibitors targeting Snail1 are scarce, inhibitors targeting Snail1-induced EMT have demonstrated promising results (84, 85). For instance, Entestat (ENT) can reverse Snail1-induced EMT, leading to increased E-cadherin expression and decreased levels of Twist, Snail, and other EMT-TFs, thereby reducing metastatic potential (86). ZEB1 acts as a key regulator, functioning as both an activator and repressor of target genes, depending on its interaction with the CDH1 promoter, miR-190 promoter, and TGF-β signaling intermediates like Smad, p300, and P/CAF (87). Twist1 is recognized as a key regulator of oncogenesis and metastasis. During EMT, Twist1 promotes the expression of EMT-related genes, such as type I collagen and N-cadherin, by directly binding to their promoters (88), enabling epithelial cells to transition to a mesenchymal phenotype. Twist1 is also crucial in regulating intercellular adhesion by influencing downstream targets like E-cadherin. Twist1 promotes EMT by inhibiting E-cadherin expression through Snail1 activity (89). In smokers, exposure to the nicotine-derived carcinogen nitrosamine ketone (NNK) upregulates Twist mRNA and protein expression, which correlates with increased migration and invasion of lung cancer cells. This underscores Twist’s role in regulating NNK-induced changes in EMT marker expression in lung cancer (90).

With expanding research on EMT, numerous TFs have emerged as novel EMT regulators, such as specificity protein 1 (SP1) and E2F1. Recent studies highlight E2F1 as a pivotal TF for cell cycle progression in cancer, closely linked to metastasis. In NSCLC tissues and cell lines, E2F1 is notably upregulated and controls ZEB2 expression via an E2F1 binding site on the ZEB2 promoter, ultimately driving EMT and enhancing tumor invasion and metastasis (91, 92). SP1, part of a TF family that includes Sp2, Sp3, and Sp4, is critical for various biological functions such as cell growth, differentiation, apoptosis, and carcinogenesis, activating numerous cellular genes (93). In lung adenocarcinoma (LADC), aberrant SP1 expression induces EMT (94). Specifically, SP1-activated SGPP2 promotes LADC cell proliferation and invasion while inhibiting apoptosis (95). SP1 also functions as a direct target of miR-145-5p in NSCLC, where its overexpression decreases drug sensitivity, promotes EMT, and heightens drug resistance in cancer cells (96). As more EMT-related markers are identified, these insights pave the way for improved therapeutic protocols for cancer treatment.