Yijie Xie1,2
I. Ho1,2
Zhipeng Liu1,2
Keyu Chen1,2
Minjie Zhou1,2
Guodong Ha1,2
Lincheng Duan1,2
Zhengyu Zhao1,2*
Dingjun Cai1,2*- 1Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- 2Key Laboratory of Acupuncture for Senile Disease (Chengdu University of Traditional Chinese Medicine (TCM)), Ministry of Education/Acupuncture and Chronobiology Key Laboratory of Sichuan Province, Chengdu, China
Melanoma is the most aggressive form of skin cancer. Although immune checkpoint inhibitors (ICIs) have led to major therapeutic breakthroughs, monotherapy remains limited by suboptimal response rates and pronounced resistance. In recent years, combination strategies integrating ICIs with anti-angiogenic agents have demonstrated substantial synergistic antitumor potential. This review systematically summarizes the mechanisms underlying this synergy, including cross-regulation between immune checkpoints and angiogenic factors (such as VEGF and ANG-2), the remodeling of the tumor immune microenvironment by anti-angiogenic agents, and feedback regulation of angiogenesis by ICIs. Preclinical studies indicate that such combinations can induce vascular normalization and enhance T-cell infiltration, thereby reversing immunosuppression. Subsequently, multiple clinical studies have confirmed that, compared with ICI monotherapy, combination therapy provides superior efficacy and acceptable safety in patients with advanced, mucosal, acral, and even brain-metastatic melanoma. Although the combined approach may increase adverse events such as cardiovascular complications and dermatologic toxicity, these risks can be controlled through multidisciplinary management. Overall, ICI-based combination therapy with anti-angiogenic agents represents a promising therapeutic paradigm for melanoma. Future research should focus on biomarker discovery and optimization of individualized precision strategies to maximize patient survival benefits.
1 Introduction
Melanoma, the most aggressive form of cutaneous malignancy, has shown a rapidly rising global incidence over the past five decades (1), and its onset and progression are closely associated with dysregulation of the immune system (2). In recent years, targeted therapies—most notably immune checkpoint inhibitors (ICIs) and anti-angiogenic agents—have provided new therapeutic options for patients with advanced melanoma (3). However, significant challenges persist in clinical practice: approximately 50% of patients exhibit no response to checkpoint inhibition (2), and disease progression remains common among those with metastatic melanoma even after receiving treatment (4) Patients with multifocal or disseminated lesions face particularly high mortality risks (4). These realities underscore the limitations of current therapeutic strategies and highlight the urgent need to develop novel combination treatment approaches.
Although ICIs (such as antibodies targeting PD-1, PD-L1, or CTLA-4) can reactivate immune pathways and promote melanoma rejection (5), their overall clinical efficacy remains suboptimal (6). Evidence shows that only a subset of patients benefits from ICI monotherapy (7), with substantial inter-individual variability in treatment response (8). Such variability is influenced by multiple factors—for example, mitochondrial dysfunction in tumor cells may affect their sensitivity to PD-1 inhibitors (6). Moreover, no reliable predictive biomarkers (e.g., tumor-associated antibodies) are currently available to accurately identify patients who are most likely to benefit from ICIs (9), further limiting the clinical application and efficacy improvement of monotherapy.
The combined use of anti-angiogenic agents and ICIs offers a new strategy to overcome existing therapeutic barriers in cancer treatment (10). The theoretical basis of this approach lies in their potential synergistic antitumor effects: ICIs block immune-escape signaling, while anti-angiogenic agents target the tumor-feeding vascular system (10). Studies have shown that anti-angiogenic agents can suppress the immunosuppressive features associated with angiogenesis and enhance antitumor immunity (7). This combination strategy is expected to increase the depth and durability of therapeutic responses, improve tumor control, and extend patient survival (11). This combination strategy is expected to increase the depth and durability of therapeutic responses, improve tumor control, and extend patient survival (3, 12).
Literature for this review was identified through searches of PubMed, Web of Science, and Embase up to November 2025. Key search terms included “melanoma”,”immune checkpoint inhibitors”, “anti-angiogenic therapy”, “VEGF”, “ANG2”, and “tumor microenvironment”. Both preclinical and clinical studies were considered, with emphasis on phase I–II trials, translational studies, and landmark mechanistic reports relevant to immune–vascular crosstalk. Non-English articles, single-agent monotherapy studies, case reports, reviews, or meta-analyses without original data were excluded. After title/abstract screening and full-text review, the most pertinent and high-quality evidence was synthesized to support the discussions in this review.
2 Synergistic mechanisms of combination therapy
2.1 Cross-regulation between ICIs and angiogenic factors
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).
2.2 Immunomodulatory effects of anti-angiogenic agents on the tumor microenvironment
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).
2.3 Feedback regulation of angiogenesis by ICIs
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).
Figure 1. Synergistic mechanisms of combination therapy with icis and anti-angiogenic agents in tumor treatment. Created in biorender.
3 Evidence from preclinical studies
Multiple preclinical studies based on animal models have demonstrated clear synergistic antitumor effects of combining ICIs with anti-angiogenic agents in melanoma. In subcutaneous and left ventricular melanoma models, dual targeting of angiogenesis and immune checkpoints significantly improved control of both intracranial and extracranial disease (19). Further investigations revealed that in subcutaneous melanoma models, the VEGFR2-targeting anti-angiogenic agent DC101 optimized the tumor vascular microenvironment and immune-cell infiltration while upregulating PD-1/PD-L1 expression, thereby creating a tumor milieu favorable for subsequent combination treatment with ICIs (22). Another key mechanistic study focused on inhibitors of angiopoietin-2 (ANG-2). By targeting the ANG-2/TIE2 signaling axis, these inhibitors repair damaged vessels at the tumor margin, reduce vascular leakage, and promote vessel normalization, thereby removing the physical barriers that impede CD8+ T-cell infiltration into the tumor core. Simultaneously, treatment decreases Treg proportions and drives macrophage polarization toward the M1 phenotype, enhancing CD8+ T-cell cytotoxicity. Ultimately, ANG-2 inhibition synergizes with anti-PD-1 therapy to reverse immune resistance and improve therapeutic efficacy (23). In addition, the natural compound steppogenin (a 2’-hydroxyflavanone) has shown significant synergy when combined with anti-PD-1 antibodies. Steppogenin induces vascular normalization through modulation of the DLL4–NOTCH1 pathway, thereby improving T-cell infiltration and antitumor activity. This study not only validates the antitumor efficacy of the combination regimen but also provides preclinical evidence supporting the use of low-toxicity natural anti-angiogenic compounds in combination with ICIs (24). Collectively, these preclinical findings consistently indicate that anti-angiogenic therapy–induced vascular normalization can effectively improve the tumor immune microenvironment and enhance the response to ICIs, providing important theoretical support for the clinical translation of this combination strategy.
4 Clinical advances
4.1 Overview of published combination regimens
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).
Table 1. Clinical trials of ICIs and anti-angiogenic agents in melanoma.
4.2 Differences in the efficacy of various anti-angiogenic agents
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.
Table 2. Candidate biomarkers for predicting response to combination therapy with ICIs and anti-angiogenic agents in melanoma.
5 Safety analysis and management of adverse events
5.1 Toxicity profile of combination therapy
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).
5.2 Monitoring and management of special adverse events
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.
6 Conclusion
Combination regimens involving immune checkpoint inhibitors (ICIs) and anti-angiogenic agents represent a highly promising new paradigm in the treatment of melanoma. This review highlights that the core advantage of this strategy lies in its ability to remodel the tumor immune microenvironment through the synergistic modulation of the “immune–vascular axis,” thereby promoting vascular normalization and enhancing T-cell infiltration. These effects help overcome therapeutic resistance and improve treatment efficacy. Clinical studies have demonstrated that such combination strategies achieve superior efficacy and safety compared with monotherapies across multiple challenging melanoma subtypes, including advanced, mucosal, acral melanoma, and brain metastases.
Despite its promising outlook, several key challenges remain in this field:
1. Most current clinical evidence is derived from phase II studies and small-sample trials, lacking validation from large-scale phase III randomized controlled trials. Therefore, the long-term efficacy and safety of this strategy require further confirmation.
2. Optimal sequencing and dosing regimens for different drug combinations remain undefined, necessitating further optimization.
3. Combination therapy may increase the risk of adverse events, particularly cardiovascular and dermatologic toxicities, imposing higher demands on clinical monitoring and management.
Future research should aim to advance the precision and individualization of this therapeutic strategy. Key directions include: conducting in-depth mechanistic studies to identify biomarkers that can predict efficacy and toxicity (such as specific angiogenic factors, immune cell subsets, or microbiome signatures) and integrating them with established clinical prognostic factors (e.g., serum lactate dehydrogenase, LDH); designing rigorous, large-scale clinical trials to establish optimal therapeutic models; and implementing multidisciplinary collaborative management systems in clinical practice. Special attention should be given to monitoring and dose adjustment for vulnerable patient populations. Through these approaches, it will be possible to control toxicity while maximizing survival benefits, ultimately leading to the maturation and standardization of this highly promising therapeutic strategy.
Author contributions
YX: Visualization, Methodology, Conceptualization, Writing – original draft. IH: Validation, Formal analysis, Writing – original draft. ZL: Validation, Writing – original draft, Formal analysis. KC: Writing – original draft, Data curation, Investigation. MZ: Data curation, Writing – original draft, Investigation. GH: Supervision, Writing – original draft. LD: Visualization, Writing – original draft. ZZ: Supervision, Writing – review & editing, Conceptualization. DC: Writing – review & editing, Conceptualization, Supervision.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by a grant from the Chengdu Municipal Health Commission 2024 Commission and University Joint Innovation Fund Project (WXLH202405010).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. Raimondi S, Suppa M, and Gandini S. Melanoma epidemiology and sun exposure. Acta Derm Venereol. (2020) 100:adv00136. doi: 10.2340/00015555-3491
2. Kumar P, Brazel D, DeRogatis J, Valerin JBG, Whiteson K, Chow WA, et al. The cure from within? A review of the microbiome and diet in melanoma. Cancer Metastasis Rev. (2022) 41:261–80. doi: 10.1007/s10555-022-10029-3
3. Xu J, Tian Y, Zhao B, Hu D, Wu S, Ma J, et al. Gut microbiome influences efficacy of endostatin combined with pd-1 blockade against colorectal cancer. Mol BioMed. (2024) 5:37. doi: 10.1186/s43556-024-00200-3
4. Hao X, Falo Iii LD, Chen G, Zhang J, Carey CD, Storkus WJ, et al. Skin immunization for effective treatment of multifocal melanoma refractory to pd1 blockade and braf inhibitors. J Immunother Cancer. (2021) 9. doi: 10.1136/jitc-2020-001179
5. Hossain SM, Gimenez G, Stockwell PA, Tsai P, Print CG, Rys J, et al. Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures. Front Immunol. (2022) 13:955063. doi: 10.3389/fimmu.2022.955063
6. Du F, Yang LH, Liu J, Wang J, Fan L, Duangmano S, et al. The role of mitochondria in the resistance of melanoma to pd-1 inhibitors. J Transl Med. (2023) 21:345. doi: 10.1186/s12967-023-04200-9
7. Huinen ZR, Huijbers EJM, van Beijnum JR, Nowak-Sliwinska P, and Griffioen AW. Anti-angiogenic agents - overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol. (2021) 18:527–40. doi: 10.1038/s41571-021-00496-y
8. Pomeranz Krummel DA, Nasti TH, Kaluzova M, Kallay L, Bhattacharya D, Melms JC, et al. Melanoma cell intrinsic gaba(a) receptor enhancement potentiates radiation and immune checkpoint inhibitor response by promoting direct and T cell-mediated antitumor activity. Int J Radiat Oncol Biol Phys. (2021) 109:1040–53. doi: 10.1016/j.ijrobp.2020.10.025
9. de Joode K, Veenbergen S, Kransse C, Kortleve D, Debets R, Mathijssen RHJ, et al. Suitability of tumor-associated antibodies as predictive biomarker for response to immune checkpoint inhibitors in patients with melanoma: A short report. J Immunother Cancer. (2023) 11. doi: 10.1136/jitc-2022-006467
10. Brest P, Mograbi B, Pagès G, Hofman P, and Milano G. Checkpoint inhibitors and anti-angiogenic agents: A winning combination. Br J Cancer. (2023) 129:1367–72. doi: 10.1038/s41416-023-02437-1
11. Dummer R, Ascierto PA, Nathan P, Robert C, and SChadendorf D. Rationale for immune checkpoint inhibitors plus targeted therapy in metastatic melanoma: A review. JAMA Oncol. (2020) 6:1957–66. doi: 10.1001/jamaoncol.2020.4401
12. Hu H, Chen Y, Tan S, Wu S, Huang Y, Fu S, et al. The research progress of antiangiogenic therapy, immune therapy and tumor microenvironment. Front Immunol. (2022) 13:802846. doi: 10.3389/fimmu.2022.802846
13. Sherafat NS, Keshavarz A, Mardi A, Mohammadiara A, Aghaei M, Aghebati-Maleki L, et al. Rationale of using immune checkpoint inhibitors (Icis) and anti-angiogenic agents in cancer treatment from a molecular perspective. Clin Exp Med. (2025) 25:238. doi: 10.1007/s10238-025-01751-7
14. Khattak MA, Abed A, Reid AL, McEvoy AC, Millward M, Ziman M, et al. Role of serum vascular endothelial growth factor (Vegf) as a potential biomarker of response to immune checkpoint inhibitor therapy in advanced melanoma: results of a pilot study. Front Oncol. (2020) 10:1041. doi: 10.3389/fonc.2020.01041
15. Liu N, Liu M, Fu S, Wang J, Tang H, Isah AD, et al. Ang2-targeted combination therapy for cancer treatment. Front Immunol. (2022) 13:949553. doi: 10.3389/fimmu.2022.949553
16. Xu Q and Shao D. Leveraging the synergy between anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system cancers. Front Immunol. (2024) 15:1487610. doi: 10.3389/fimmu.2024.1487610
17. Shen S, Hong Y, Huang J, Qu X, Sooranna SR, Lu S, et al. Targeting pd-1/pd-L1 in tumor immunotherapy: mechanisms and interactions with host growth regulatory pathways. Cytokine Growth Factor Rev. (2024) 79:16–28. doi: 10.1016/j.cytogfr.2024.08.001
18. Bourhis M, Palle J, Galy-Fauroux I, and Terme M. Direct and indirect modulation of T cells by vegf-a counteracted by anti-angiogenic treatment. Front Immunol. (2021) 12:616837. doi: 10.3389/fimmu.2021.616837
19. Tran TT, Caulfield J, Zhang L, Schoenfeld D, Djureinovic D, Chiang VL, et al. Lenvatinib or anti-vegf in combination with anti-pd-1 differentially augments antitumor activity in melanoma. JCI Insight. (2023) 8. doi: 10.1172/jci.insight.157347
20. Cai Z, Meng K, Yu T, Xi Y, Yuan Z, Wang X, et al. Ifn-Γ-mediated suppression of angpt2-tie2 in endothelial cells facilitates tumor vascular normalization during immunotherapy. Front Immunol. (2025) 16:1551322. doi: 10.3389/fimmu.2025.1551322
21. Zheng W, Qian C, Tang Y, Yang C, Zhou Y, Shen P, et al. Manipulation of the crosstalk between tumor angiogenesis and immunosuppression in the tumor microenvironment: insight into the combination therapy of anti-angiogenesis and immune checkpoint blockade. Front Immunol. (2022) 13:1035323. doi: 10.3389/fimmu.2022.1035323
22. Wang Z, Shi X, Zhao Y, Zhou J, Zhang S, Wang J, et al. Dc101, an anti-vegfr2 agent, promotes high-endothelial venule formation and immune infiltration versus sar131675 and fruquintinib. Biochem Biophys Res Commun. (2023) 661:10–20. doi: 10.1016/j.bbrc.2023.04.018
23. Park HR, Shiva A, Cummings P, Kim S, Kim S, Lee E, et al. Angiopoietin-2-dependent spatial vascular destabilization promotes T-cell exclusion and limits immunotherapy in melanoma. Cancer Res. (2023) 83:1968–83. doi: 10.1158/0008-5472.Can-22-2838
24. You J, Ha S, Kim D, Kim HG, Kim SH, Jeong JH, et al. The inhibition of endothelial dll4-notch1 signaling by 2’-hydroxyflavanone enhances anti-pd-1 therapy in melanoma. Arch Pharm Res. (2025) 48:351–64. doi: 10.1007/s12272-025-01539-z
25. Song Y, Fu Y, Xie Q, Zhu B, Wang J, and Zhang B. Anti-angiogenic agents in combination with immune checkpoint inhibitors: A promising strategy for cancer treatment. Front Immunol. (2020) 11:1956. doi: 10.3389/fimmu.2020.01956
26. Ott PA, Nazzaro M, Pfaff KL, Gjini E, Felt KD, Wolff JO, et al. Combining ctla-4 and angiopoietin-2 blockade in patients with advanced melanoma: A phase I trial. J Immunother Cancer. (2021) 9. doi: 10.1136/jitc-2021-003318
27. Quaresmini D and Guida M. Neoangiogenesis in melanoma: an issue in biology and systemic treatment. Front Immunol. (2020) 11:584903. doi: 10.3389/fimmu.2020.584903
28. Mao L, Fang M, Chen Y, Wei X, Cao J, Lin J, et al. Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: A multicenter, open-label, single-arm phase ii study. Clin Cancer Res. (2022) 28:4642–8. doi: 10.1158/1078-0432.Ccr-22-1528
29. Dai J, Xu T, Li L, Fang M, Lin J, Cao J, et al. Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: 3-year survival update and multi-omics analysis. Clin Transl Med. (2025) 15:e70169. doi: 10.1002/ctm2.70169
30. Weiss SA, Djureinovic D, Wei W, Tran T, Austin M, Markowitz J, et al. Phase ii trial of pembrolizumab in combination with bevacizumab for untreated melanoma brain metastases. J Clin Oncol. (2025) 43:1685–94. doi: 10.1200/jco-24-02219
31. Arance A, de la Cruz-Merino L, Petrella TM, Jamal R, Ny L, Carneiro A, et al. Phase ii leap-004 study of lenvatinib plus pembrolizumab for melanoma with confirmed progression on a programmed cell death protein-1 or programmed death ligand 1 inhibitor given as monotherapy or in combination. J Clin Oncol. (2023) 41:75–85. doi: 10.1200/jco.22.00221
32. Lian B, Li Z, Wu N, Li M, Chen X, Zheng H, et al. Phase ii clinical trial of neoadjuvant anti-pd-1 (Toripalimab) combined with axitinib in resectable mucosal melanoma. Ann Oncol. (2024) 35:211–20. doi: 10.1016/j.annonc.2023.10.793
33. Mao L, Lian B, Li C, Bai X, Zhou L, Cui C, et al. Camrelizumab plus apatinib and temozolomide as first-line treatment in patients with advanced acral melanoma: the cap 03 phase 2 nonrandomized clinical trial. JAMA Oncol. (2023) 9:1099–107. doi: 10.1001/jamaoncol.2023.1363
34. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. (2014) 2:632–42. doi: 10.1158/2326-6066.Cir-14-0053
35. Malekan M, Haass NK, Rokni GR, Gholizadeh N, Ebrahimzadeh MA, and Kazeminejad A. Vegf/vegfr axis and its signaling in melanoma: current knowledge toward therapeutic targeting agents and future perspectives. Life Sci. (2024) 345:122563. doi: 10.1016/j.lfs.2024.122563
36. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, and Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. (2018) 15:325–40. doi: 10.1038/nrclinonc.2018.29
37. Sheng X, Yan X, Chi Z, Si L, Cui C, Tang B, et al. Axitinib in combination with toripalimab, a humanized immunoglobulin G(4) monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma: an open-label phase ib trial. J Clin Oncol. (2019) 37:2987–99. doi: 10.1200/jco.19.00210
38. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous nsclc. N Engl J Med. (2018) 378:2288–301. doi: 10.1056/NEJMoa1716948
39. Plimack ER, Powles T, Stus V, Gafanov R, Nosov D, Waddell T, et al. Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of the phase 3 keynote-426 study. Eur Urol. (2023) 84:449–54. doi: 10.1016/j.eururo.2023.06.006
40. Claps G, Faouzi S, Quidville V, Chehade F, Shen S, Vagner S, et al. The multiple roles of ldh in cancer. Nat Rev Clin Oncol. (2022) 19:749–62. doi: 10.1038/s41571-022-00686-2
41. Zhao M, Qian Y, He L, Peng T, Wang H, Wang X, et al. Lactate-mediated histone lactylation promotes melanoma angiogenesis via il-33/st2 axis. Cell Death Dis. (2025) 16:701. doi: 10.1038/s41419-025-08023-y
42. Carlino MS, Larkin J, and Long GV. Immune checkpoint inhibitors in melanoma. Lancet. (2021) 398:1002–14. doi: 10.1016/s0140-6736(21)01206-x
43. le Noble FAC, Mourad JJ, Levy BI, and Struijker-Boudier HAJ. Vegf (Vascular endothelial growth factor) inhibition and hypertension: does microvascular rarefaction play a role? Hypertension. (2023) 80:901–11. doi: 10.1161/hypertensionaha.122.19427
44. Tian H, Wang X, Lian B, Yan X, Si L, Chi Z, et al. Safety profile of immunotherapy combined with antiangiogenic therapy in patients with melanoma: analysis of three clinical studies. Front Pharmacol. (2021) 12:747416. doi: 10.3389/fphar.2021.747416
45. Wang Y, Cui C, Deng L, Wang L, and Ren X. Cardiovascular toxicity profiles of immune checkpoint inhibitors with or without angiogenesis inhibitors: A real-world pharmacovigilance analysis based on the faers database from 2014 to 2022. Front Immunol. (2023) 14:1127128. doi: 10.3389/fimmu.2023.1127128
46. Crocetto F, Ferro M, Buonerba C, Bardi L, Dolce P, Scafuri L, et al. Comparing cardiovascular adverse events in cancer patients: A meta-analysis of combination therapy with angiogenesis inhibitors and immune checkpoint inhibitors versus angiogenesis inhibitors alone. Crit Rev Oncol Hematol. (2023) 188:104059. doi: 10.1016/j.critrevonc.2023.104059
47. Gergely TG, Drobni ZD, Sayour NV, Ferdinandy P, and Varga ZV. Molecular fingerprints of cardiovascular toxicities of immune checkpoint inhibitors. Basic Res Cardiol. (2025) 120:187–205. doi: 10.1007/s00395-024-01068-8
48. Zheng J, Yi Y, Tian T, Luo S, Liang X, and Bai Y. Ici-induced cardiovascular toxicity: mechanisms and immune reprogramming therapeutic strategies. Front Immunol. (2025) 16:1550400. doi: 10.3389/fimmu.2025.1550400
49. Eswaran H, Kasthuri RR, Bendapudi PK, Khorana AA, Kasthuri RS, van Es N, et al. Cabozantinib and thromboembolism in patients with cancer: A systematic review, meta-analysis and retrospective study. Blood Adv. (2025) 10:301–14. doi: 10.1182/bloodadvances.2025018001
50. Rankin S, Elyan B, Jones R, Venugopal B, Mark PB, Lees JS, et al. Cardiovascular Eligibility Criteria And adverse Event Reporting In combined Immune Checkpoint And vegf Inhibitor Trials. JACC CardioOncol. (2024) 6:267–79. doi: 10.1016/j.jaccao.2023.12.010
51. Nikolaou VA, Apalla Z, Carrera C, Fattore D, Sollena P, Riganti J, et al. Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: A multicentre study from the european academy of dermatology and venereology task force of dermatology for cancer patients. Br J Dermatol. (2022) 187:962–9. doi: 10.1111/bjd.21781
52. Collins LK, Chapman MS, Carter JB, and Samie FH. Cutaneous adverse effects of the immune checkpoint inhibitors. Curr Probl Cancer. (2017) 41:125–8. doi: 10.1016/j.currproblcancer.2016.12.001
53. Janssen JC, van Dijk B, Hoeijmakers LL, Grünhagen DJ, Bramer WM, Verhoef C, et al. Local administration of immunotherapy for patients with skin cancer: A systematic review. Cancer Treat Rev. (2024) 131:102848. doi: 10.1016/j.ctrv.2024.102848
54. Dolladille C, Akroun J, Morice PM, Dompmartin A, Ezine E, Sassier M, et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: A safety meta-analysis. Eur Heart J. (2021) 42:4964–77. doi: 10.1093/eurheartj/ehab618
55. Leone P, Solimando AG, Fasano R, Argentiero A, Malerba E, Buonavoglia A, et al. The evolving role of immune checkpoint inhibitors in hepatocellular carcinoma treatment. Vaccines (Basel). (2021) 9. doi: 10.3390/vaccines9050532
56. Patel AB, Farooq S, Welborn M, Amaria RN, Chon SY, Diab A, et al. Cutaneous adverse events in 155 patients with metastatic melanoma consecutively treated with anti-ctla4 and anti-pd1 combination immunotherapy: incidence, management, and clinical benefit. Cancer. (2022) 128:975–83. doi: 10.1002/cncr.34004
57. Gulati N, Donnelly D, Qian Y, Moran U, Johannet P, Zhong J, et al. Revisiting the association between skin toxicity and better response in advanced cancer patients treated with immune checkpoint inhibitors. J Transl Med. (2020) 18:430. doi: 10.1186/s12967-020-02612-5
58. Plaçais L, Dalle S, Dereure O, Trabelsi S, Dalac S, Legoupil D, et al. Risk of iraes in patients with autoimmune diseases treated by immune checkpoint inhibitors for stage iii or iv melanoma: results from a matched case-control study. Ann Rheum Dis. (2022) 81:1445–52. doi: 10.1136/ard-2022-222186
59. Ju M, Zhang J, Deng Z, Wei M, Ma L, Chen T, et al. Prophylactic il-23 blockade uncouples efficacy and toxicity in dual ctla-4 and pd-1 immunotherapy. J Immunother Cancer. (2024) 12. doi: 10.1136/jitc-2024-009345
60. Qi Z, Yang Q, Wang Y, Song Y, and Deng Y. Vicious-cycle-breaking antiangiogenic nano-delivery systems potentiate and simplify the tumor vascular normalization strategy. Int J Pharm. (2025) 681:125788. doi: 10.1016/j.ijpharm.2025.125788
61. Giustozzi M, Proietti G, Becattini C, Roila F, Agnelli G, and Mandalà M. Ich in primary or metastatic brain cancer patients with or without anticoagulant treatment: A systematic review and meta-analysis. Blood Adv. (2022) 6:4873–83. doi: 10.1182/bloodadvances.2022008086
62. Rodriguez-Baena FJ, Marquez-Galera A, Ballesteros-Martinez P, Castillo A, Diaz E, Moreno-Bueno G, et al. Microglial reprogramming enhances antitumor immunity and immunotherapy response in melanoma brain metastases. Cancer Cell. (2025) 43:413–27.e9. doi: 10.1016/j.ccell.2025.01.008
63. Fares J, Ulasov I, Timashev P, and Lesniak MS. Emerging principles of brain immunology and immune checkpoint blockade in brain metastases. Brain. (2021) 144:1046–66. doi: 10.1093/brain/awab012
Keywords: anti-angiogenic agents, combination therapy, immune checkpoint inhibitors, melanoma, tumor microenvironment
Citation: Xie Y, Ho I, Liu Z, Chen K, Zhou M, Ha G, Duan L, Zhao Z and Cai D (2026) Tumor immune-vascular crosstalk: synergy and translation of immune checkpoint inhibitors and anti-angiogenic agents in melanoma. Front. Immunol. 17:1760044. doi: 10.3389/fimmu.2026.1760044
Received: 03 December 2025; Accepted: 27 January 2026; Revised: 07 January 2026;
Published: 12 February 2026.
Edited by:
Max Levin, University of Gothenburg, SwedenReviewed by:
Marinaldo Pacífico Cavalcanti Neto, Federal University of Rio de Janeiro, BrazilCopyright © 2026 Xie, Ho, Liu, Chen, Zhou, Ha, Duan, Zhao and Cai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhengyu Zhao, emhhb3poZW5neXVAY2R1dGNtLmVkdS5jbg==; Dingjun Cai, ZGpjYWlAY2R1dGNtLmVkdS5jbg==