ICIs exert their effects by blocking signaling pathways that enable tumor cells to evade immune surveillance, whereas anti-angiogenic agents target the aberrantly activated tumor vasculature, restricting its supply of nutrients and oxygen (13). Extensive cross-regulatory interactions exist between the two at the molecular level. The vascular endothelial growth factor (VEGF) pathway has been identified as the “vascular counterpart” of immune checkpoints, and this structural analogy forms the theoretical basis for combination therapy (7). In melanoma, VEGF not only promotes angiogenesis but also directly suppresses T-cell function, whereas ICIs can reverse this immunosuppressive state (14). Members of the angiopoietin family, such as ANG-2, disrupt vascular stability, promote pathological angiogenesis, and act synergistically with VEGF to drive tumor progression (15). Furthermore, a bidirectional regulatory relationship exists between the PD-1/PD-L1 axis and VEGF signaling: PD-L1 expression can induce VEGF secretion, while VEGF can upregulate PD-L1 expression, forming a positive feedback loop that facilitates tumor progression (16, 17).

Anti-angiogenic agents can profoundly reshape the immunosuppressive characteristics of the tumor microenvironment. By inhibiting the VEGF or Ang2/Tie2 signaling pathways, these agents reduce the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while enhancing the infiltration and activation of cytotoxic T lymphocytes within tumor tissues (15, 18). Preclinical studies further demonstrate that anti-angiogenic therapy induces “normalization” of tumor vessel structure and function in melanoma models, improving intratumoral perfusion and oxygenation, thereby facilitating the trafficking and functional activity of immune effector cells (19). It is noteworthy that different classes of anti-angiogenic agents exert distinct regulatory effects on the immune microenvironment. For example, while lenvatinib and anti-VEGF antibodies both reduce intratumoral vascular density, their effects on the stability of endothelial cells within the blood–brain barrier differ (19).

ICIs not only directly modulate the immune system but also regulate tumor angiogenesis through multiple mechanisms. PD-1/PD-L1 inhibitors can downregulate the secretion of pro-angiogenic factors—such as VEGF and FGF—by tumor cells and tumor-associated fibroblasts (16). In melanoma animal models, anti-PD-1 therapy decreases tumor vascular density and enhances vessel maturation, and this vascular normalization effect is closely associated with therapeutic response (19). Additionally, ICIs promote T-cell activation and stimulate the secretion of cytokines such as interferon-γ (IFN-γ), which further suppress endothelial cell proliferation and migration, thereby strengthening anti-angiogenic effects (20). Together, these mechanisms constitute a bidirectional “immune–vascular axis,” providing a strong scientific rationale for combination therapy (21). Recent studies also suggest that the gut microbiota may influence the efficacy of combination regimens by modulating angiogenesis and ICI-mediated antitumor activity, positioning it as a novel factor affecting treatment outcomes (3).

(Figure 1 summarizes the mechanistic interplay between immune checkpoints and angiogenic pathways, the resulting microenvironmental remodeling, and the rationale for corresponding clinical combination strategies).

In recent years, combination regimens involving ICIs and anti-angiogenic agents have achieved substantial progress in the treatment of melanoma. Current clinical studies mainly focus on combining PD-1/PD-L1 inhibitors (such as nivolumab and pembrolizumab) or CTLA-4 inhibitors (such as ipilimumab) with VEGFR-targeting agents (such as bevacizumab and apatinib) or anti-Ang2 agents (such as MEDI3617) (25, 26). This strategy, which simultaneously blocks immune evasion pathways and tumor angiogenesis, has demonstrated synergistic efficacy superior to monotherapies (27).

The combination of the anti-PD-L1 inhibitor atezolizumab and the VEGFR monoclonal antibody bevacizumab achieved promising results in a phase II trial involving patients with advanced melanoma, with an objective response rate (ORR) of 45.0%, a disease control rate (DCR) of 65%, and a median progression-free survival (PFS) of 8.2 months (28). Safety was manageable, and subsequent three-year follow-up data further confirmed the durability of this regimen (29).

In a phase II trial evaluating bevacizumab plus pembrolizumab in treatment-naïve melanoma brain metastasis (MBM), 37 patients received four cycles of combined therapy every three weeks, followed by up to two years of pembrolizumab monotherapy. In this phase II non-randomized trial of treatment-naïve melanoma brain metastasis (MBM), the ORR reached 54.1%, median PFS was 1.2 years, and mOS was 4.3 years—results that require validation in large-scale phase III randomized controlled trials (RCTs). Higher baseline vascular density and smaller increases in circulating ANG-2 during treatment correlated with response. The combination was well tolerated and demonstrated significant efficacy in untreated MBM patients (30).

Numerous phase II studies have confirmed that ICIs combined with small-molecule TKIs targeting the VEGF/VEGFR pathway show remarkable potential in advanced melanoma. The phase II LEAP-004 study suggested that pembrolizumab combined with lenvatinib achieved an ORR of 21.4%, a PFS of 4.2 months, and an mOS of 14.0 months in patients with disease progression after prior ICI therapy, providing a potential second-line option for this refractory population. However, these results are preliminary and warrant confirmation in randomized controlled trials (31).

In resectable mucosal melanoma, which typically exhibits poor prognosis, neoadjuvant therapy with toripalimab (anti–PD-1) plus axitinib (anti-angiogenic agent) demonstrated notable efficacy: among 24 patients who underwent surgery, the ORR reached 33.3%, including 16.7% pathological complete responses and 16.7% pathological partial responses. This regimen significantly remodeled the tumor immune microenvironment, with marked increases in intratumoral CD3⁺ and CD3⁺CD8⁺ tumor-infiltrating lymphocytes, especially among patients who achieved pathological responses. The regimen was well tolerated, with grade 3–4 adverse events occurring in only 27.5% of patients and no treatment-related deaths, thus providing an effective and safe neoadjuvant option and laying groundwork for optimizing perioperative therapy for this melanoma subtype (32).

For advanced acral melanoma—an ICI-insensitive subtype with low tumor mutational burden(TMB)—the triplet regimen of camrelizumab (anti–PD-1), apatinib (VEGFR2 inhibitor), and temozolomide (chemotherapy) demonstrated substantial efficacy and acceptable safety as first-line therapy. The ORR reached 64.0%, and PFS reached 18.4 months, overcoming historical limitations in treatment effectiveness and emerging as a potential first-line therapeutic option for this ICI-insensitive subtype, supported by phase II data (33).

In a phase I trial, 46 patients with advanced melanoma received combined ipilimumab (anti–CTLA-4) and bevacizumab (anti-VEGF). The ORR was 19.6%, DCR was 67.4%, and mOS reached 25.1 months. Post-treatment tumor samples showed endothelial activation and increased infiltration of CD8⁺T cells and macrophages (34). Building upon this trial, another phase I study enrolled 15 patients treated with tremelimumab (CTLA-4 antibody) and the Ang2 inhibitor MEDI3617. Results demonstrated acceptable safety, with a DCR of 40% and an mOS of 15.4 months. Treatment was associated with increased circulating CD4⁺ and CD8⁺T cells expressing activation markers (ICOS⁺, HLA-DR⁺), along with elevated levels of immune-activating (IL-2) and immunoregulatory (IL-10) cytokines, suggesting robust antitumor immune activation and maintenance of immune homeostasis (26).

Collectively, these clinical findings indicate that most combination regimens exhibit significant efficacy with manageable toxicity, and some further enhance therapeutic benefit by remodeling the tumor immune microenvironment and activating antitumor immune homeostasis (Table 1).

Different VEGFR tyrosine kinase inhibitors (TKIs), such as apatinib, exhibit notable advantages in alleviating immune suppression within the tumor microenvironment by normalizing tumor vasculature and promoting T-cell infiltration (35). In contrast, anti-VEGF monoclonal antibodies (e.g., bevacizumab) primarily reduce tumor hypoxia and decrease the proportion of myeloid-derived suppressor cells (MDSCs) (36). In contrast, anti-VEGF monoclonal antibodies (e.g., bevacizumab) primarily reduce tumor hypoxia and decrease the proportion of myeloid-derived suppressor cells (MDSCs) (37). Anti-VEGF monoclonal antibodies have demonstrated significant overall survival (OS) benefits in non-small cell lung cancer (38), renal cell carcinoma (39), and have also shown encouraging activity in a phase II study of melanoma brain metastases (30). Meanwhile, anti-Ang2 agents (e.g., Ang2 inhibitors) can markedly enhance CD8⁺ T-cell infiltration into the tumor core, strengthening antitumor responses and reversing resistance to anti-PD-1 therapy (15, 23). This mechanism complements the T-cell-promoting effects of VEGFR-TKIs.

It is worth noting that Preclinical and translational studies suggest that treatment sequencing may influence efficacy; however, current evidence is largely indirect and derived from mechanistic models or non-melanoma settings, and optimal sequencing in melanoma remains to be prospectively defined (36).

In addition, the interpretation of these promising outcomes must also consider established clinical prognostic factors, such as serum lactate dehydrogenase (LDH) levels, which remain a cornerstone for risk stratification in advanced melanoma (40, 41). The promising yet variable clinical outcomes of ICI and anti-angiogenic agent combinations underscore the pressing need for predictive biomarkers to guide patient selection and sequence therapy. Here, we summarize key candidate biomarkers in Table 2.

Combination therapy with ICIs and anti-angiogenic agents, while providing synergistic antitumor effects, is also associated with unique toxicity characteristics. The increased toxicity largely arises from overlapping mechanisms: ICIs can induce autoimmune toxicities by releasing immune inhibition (42), whereas anti-angiogenic agents may lead to vascular-related adverse effects (43). Clinical studies (44) indicate that adverse events (AEs) occur more frequently with combination therapy than with PD-1 monotherapy, but the spectrum of toxicities (hepatic, endocrine, dermatologic, etc.) is similar to those observed with either agent alone, without introducing new or unexpected toxicities.

Cardiovascular toxicity is a particularly significant concern. Real-world evidence suggests that combining the two classes of drugs increases the incidence of hypertension, myocarditis, and heart failure (45). A meta-analysis of randomized controlled trials found that anti-VEGF drugs (e.g., bevacizumab) are associated with increased risk of multiple cardiovascular events, while ICIs alone do not markedly raise cardiovascular risk (46). ICI-related cardiovascular toxicities mainly include acute myocarditis, chronic inflammatory cardiomyopathy, and ischemic heart disease (47, 48), whereas anti-angiogenic agents (e.g., TKIs) disrupt vascular homeostasis, leading to hypertension, thrombosis, and elevated bleeding risk (49). Combination therapy significantly increases the incidence of hypertension, thrombotic events, and bleeding, further worsening these toxicities (45, 50).

Dermatologic toxicity is another common category of adverse events (51). Skin toxicities with ICI monotherapy—such as rash, pruritus, and depigmentation—occur in about 20–30% of patients (52, 53), lower than the 65.3% observed with combination therapy. This suggests that anti-angiogenic agents may exacerbate mucocutaneous irritation, leading to a higher incidence of skin toxicity (44).

For adverse events uniquely associated with combination therapy, targeted monitoring and management strategies are required. In the cardiovascular system, enhanced surveillance of cardiac enzymes, electrocardiograms, and cardiac imaging is recommended during treatment, with prompt intervention upon detection of abnormalities (45, 54). Hypertension, a common AE, should be managed with angiotensin-converting enzyme inhibitors or calcium channel blockers (45). A hepatocellular carcinoma study suggests evaluating baseline cardiovascular risk when combining ICIs with anti-angiogenic agents (55).

Management of dermatologic toxicities requires differentiating between types of skin involvement. For immune-related skin toxicity, mild rashes may be treated with topical corticosteroids, whereas moderate-to-severe rashes may require pausing immunotherapy and implementing systemic corticosteroids (53, 56). Importantly, cutaneous manifestations such as vitiligo may correlate with favorable treatment response and should not automatically prompt discontinuation of effective therapy (56). Studies show that patients who develop cutaneous irAEs respond better to ICIs (57), though the severity and prognostic implications of skin toxicities in combination therapy warrant further investigation. Early recognition and intervention (e.g., topical or systemic immunosuppression) are crucial for preserving quality of life.

For predicting and mitigating immune-related inflammation, patients with pre-existing autoimmune diseases (pAID) have significantly higher rates of irAEs and require enhanced autoantibody monitoring (58). Moreover, baseline peripheral inflammatory cytokine profiles—such as elevated IL-23—may predict risk of severe irAEs (59).

Regarding optimization of anti-angiogenic drug dosing and the “vascular normalization window,” precise dose adjustments are needed: insufficient dosing may promote angiogenesis, whereas excessive dosing inhibits immune-cell infiltration (7, 60). Imaging-based monitoring of tumor vascular structure (e.g., perfusion parameters) may help identify the normalization window, during which administering ICIs can reduce irAE risk (7, 60). Furthermore, bleeding risk associated with anti-angiogenic agents requires particular attention—especially in patients with brain metastases (61). These patients also need monitoring for neuroinflammation (e.g., microglial activation markers), which may relate to ICI efficacy and neurotoxicity (62, 63). Lower starting doses and extended monitoring intervals are advised for elderly patients or those with autoimmune histories (64).

Throughout treatment, establishing a multidisciplinary team—including oncology, cardiology, and dermatology specialists—is recommended to manage complex adverse events (64). Patient education should also be strengthened to ensure early recognition and timely reporting of symptoms. These integrated measures help maximize the clinical benefits of combination therapy while ensuring patient safety.