Review Article

 Emerging Vascular-Targeted Strategies for Gastric Cancer: A Novel Local Delivery Approach

 Jeong-Yoon Yang^1,2, Seo Lyn Choi^1,3, Chang-Whan Yoon^1,3,#, Jung Ho Park^1,4,#

Abstract 

Background/Objectives: Gastric cancer (GC) remains a major global health challenge and continues to demonstrate poor long-term outcomes in advanced disease despite incremental progress in biomarker-guided targeted therapy and immunotherapy. Tumor angiogenesis is a defining feature of GC biology, driving disease progression, metastatic dissemination, and therapeutic resistance through complex vascular and stromal interactions.

Methods: This review summarizes preclinical and clinical evidence on vascular-targeted therapies in gastric cancer, with emphasis on locoregional delivery strategies. We evaluated systemic anti-angiogenic and vascular-disrupting agents alongside interventional approaches, including transarterial embolization, transarterial chemoembolization, hepatic arterial infusion chemotherapy, and endoscopic ultrasound–guided intratumoral delivery, focusing on mechanisms, efficacy, safety, and integration with immunotherapy.

Results: Systemic angiogenic pathway inhibition provides modest survival benefits in advanced gastric cancer but is limited by hypoxia-driven compensatory angiogenesis and stromal adaptation. Vascular-disrupting agents directly collapse tumor vasculature yet are constrained by systemic toxicity. In contrast, locoregional vascular-targeted delivery achieves high intratumoral drug exposure with reduced systemic burden, enhancing vascular disruption and favorable tumor microenvironment modulation, with emerging evidence of synergy with immunotherapy through increased tumor necrosis and immune activation.

Conclusions: Local vascular-targeted delivery represents an emerging therapeutic paradigm in GC, leveraging interventional platforms to achieve selective vascular collapse with reduced systemic toxicity. Integration with systemic immunotherapy or anti-angiogenic agents may enhance durability of response and expand treatment options for patients unsuited to intensive chemotherapy, supporting the transition toward precision-guided, multimodal management in advanced gastric cancer.

Keywords

Gastric cancer, Tumor angiogenesis, vascular-targeted therpy, drug delivery, Immunotherapy

Introduction

Gastric cancer (GC) remains a significant global health burden, representing the fifth most common malignancy and the fourth leading cause of cancer-related mortality worldwide. The highest incidence rates are observed in East Asia, particularly in Korea, Japan, and China, where both environmental and genetic risk factors converge [1]. Despite substantial advances in early detection, endoscopic resection, and combination chemotherapy, most patients present with locally advanced or metastatic disease, with median overall survival (OS) rarely exceeding 12 months even with optimal systemic therapy [2]. The introduction of biomarker-driven targeted therapies, such as trastuzumab for HER2-positive tumors and immune checkpoint inhibitors like nivolumab for PD-L1–positive disease, has improved clinical outcomes modestly but has not fundamentally altered the fatal trajectory of advanced GC [3, 4].

A major barrier to therapeutic success lies in the unique biology of the gastric tumor microenvironment (TME), particularly the structurally abnormal and highly heterogeneous tumor vasculature that supports hypoxia, immune suppression, and resistance to systemic therapy.[5]. As illustrated in Figure 1, the stomach wall contains multiple vascularized layers, and this architectural complexity directly influences tumor angiogenesis, drug penetration, and the feasibility of localized therapeutic delivery approaches. These anatomical and microenvironmental features underscore the rationale for exploring alternative vascular-targeted therapeutic paradigms.

Figure 1. Locoregional vascular-targeted delivery strategies in gastric cancer. (A) Schematic depiction of the gross and histological organization of the stomach wall, including the mucosa, submucosa, muscularis propria, subserosa, and serosa. The figure highlights the dense vascular network within the mucosal layer, relevant to tumor angiogenesis and drug penetration. A minimally invasive local injection route is illustrated to represent emerging delivery strategies designed to administer vascular-targeted or cytotoxic agents directly to or adjacent to gastric tumors, enabling higher intratumoral drug exposure with reduced systemic toxicity. (B) Conceptual illustration of peritumoral or intralesional injection targeting the tumor microenvironment to enhance drug retention and precision delivery. (C) Application of locoregional injection in an in vivo mouse tumor model to demonstrate preclinical feasibility and evaluation of delivery efficiency and therapeutic response.

Current Systemic Therapies

The therapeutic landscape of advanced gastric cancer (GC) has evolved gradually, driven by advances in molecular stratification and targeted therapy development. Anti-angiogenic agents represent a key class within systemic treatment, with ramucirumab—the first monoclonal antibody targeting vascular endothelial growth factor receptor-2 (VEGFR-2)—establishing proof-of-concept clinical benefit. In the phase III REGARD and RAINBOW trials, ramucirumab monotherapy or combined with paclitaxel demonstrated statistically significant improvements in overall survival (OS) and progression-free survival (PFS), validating VEGFR-2 inhibition as a clinically actionable target in GC [6, 7]. However, response rates remained modest (approximately 28%), and complete responses were infrequent, highlighting intrinsic and acquired resistance to anti-angiogenic monotherapy.

Similarly, the VEGFR-2 tyrosine kinase inhibitor apatinib improved OS in chemotherapy-refractory disease (median OS: 6.5 vs. 4.7 months; HR 0.709; P = 0.0156) [8], but treatment was frequently limited by hypertension, proteinuria, and hand-foot syndrome. Collectively, clinical experience underscores a central challenge: while VEGF pathway blockade transiently suppresses tumor angiogenesis and normalizes vasculature, adaptive signaling rapidly restores perfusion.

Mechanistic studies demonstrate that VEGF inhibition induces intratumoral hypoxia and stabilization of hypoxia-inducible factor-1α (HIF-1α), driving compensatory pro-angiogenic programs involving FGF, PDGF, and angiopoietins [9, 10]. In parallel, recruitment of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) reinforces vascular regrowth and suppresses anti-tumor immunity [11]. These adaptive responses explain the limited durability of systemic anti-angiogenic therapy and provide a rationale for strategies that induce rapid and irreversible vascular collapse or synergize with immune checkpoint inhibition.

Vascular-Disrupting Agents (VDAs): Mechanistic Insights

VDAs represent a mechanistically distinct therapeutic approach that targets established tumor vasculature rather than preventing new vessel formation. Combretastatin A-4 phosphate (CA4P) is the prototypical VDA that binds to the colchicine-binding site of β-tubulin, disrupting endothelial cytoskeletal integrity. This disruption leads to endothelial cell rounding, intercellular junction loss, and subsequent vascular collapse [12, 13]. The rapid reduction in blood flow results in central necrosis within the tumor core, while a viable rim often persists at the periphery due to perfusion from normal vasculature [14]. Dynamic contrast-enhanced MRI studies in early clinical trials demonstrated marked (>50%) reductions in perfusion within hours of CA4P administration [15]. 

However, systemic administration of VDAs remains constrained by cardiovascular toxicity, including transient hypertension, QT interval prolongation, and visual disturbances. To address these challenges, combination regimens incorporating VDAs with anti-angiogenic agents or immunotherapies have been explored. Preclinical models suggest that VDAs can enhance immune infiltration by inducing tumor necrosis and releasing damage-associated molecular patterns (DAMPs), which may sensitize tumors to checkpoint blockade. Additionally, sustained-release formulations and nanoparticle-encapsulated VDAs are being investigated to enhance tumor selectivity and reduce off-target toxicity.

Figure 2. Tumor-localized injection and therapeutic response in a mouse model. Schematic illustration (left) depicts the peritumoral or intratumoral injection strategy used for localized drug delivery. Representative images from two independent tumor-bearing mice (No. 124 and No. 125) demonstrate the treatment response following a single locoregional injection. In panel (a), the injection site (red arrow) and measurable tumor mass (T) are shown immediately after administration. Panels (b) and (c) show progressive morphological tumor changes, including lesion shrinkage, scabbing, and necrosis over the treatment period. Both subjects exhibited visible tumor regression and localized tissue response consistent with vascular disruption and drug-induced necrosis. These findings support the feasibility and therapeutic potential of direct local delivery as an alternative or complementary strategy to systemic treatment in gastric cancer models.

Locoregional and Endoscopic Delivery Strategies

Locoregional delivery approaches are gaining attention as promising alternatives or adjuncts to systemic therapy in advanced or metastatic gastric cancer (GC), particularly in patients with bleeding tumors or liver-dominant metastatic disease. Transcatheter arterial embolization (TAE), transarterial chemoembolization (TACE), and hepatic arterial infusion chemotherapy (HAIC) have demonstrated feasibility and measurable clinical activity within this setting. TAE achieves high technical success (>85%) and provides effective palliation of hemorrhage [16, 17], while mitomycin-based TACE has yielded partial response rates of up to 36% [18]. HAIC, frequently incorporating oxaliplatin infusion combined with oral S-1, has demonstrated hepatic response rates approaching 40% and prolonged hepatic progression-free survival to nearly nine months [19]. Collectively, these findings support regional chemotherapy as a clinically viable modality, particularly where systemic drug exposure is insufficient or poorly tolerated.

Endoscopic ultrasound-guided fine-needle injection (EUS-FNI) represents a complementary minimally invasive strategy capable of achieving precise peritumoral or intratumoral therapeutic delivery under real-time visualization. Preclinical studies using sustained-release 5-fluorouracil (5-FU) sol-gel formulations have shown >70% complete tumor regression and induction of thrombospondin-1, an endogenous angiogenesis inhibitor [20, 21]. Early clinical pilot experience further demonstrated that localized 5-FU delivery achieved rapid hemostasis in bleeding GC while minimizing systemic toxicity. These findings illustrate the translational opportunity to leverage the anatomical accessibility of the stomach for image-guided deployment of vascular-disrupting agents and combination locoregional regimens.

Clinical Applications and Safety Considerations

Local vascular-targeted therapies offer conceptual advantages over systemic delivery by enabling high intratumoral drug exposure while limiting systemic toxicity—an especially relevant benefit for vascular-disrupting agents (VDAs) with narrow therapeutic windows. Interventional procedures such as TAE, TACE, HAIC, and EUS-FNI are repeatable, anatomically customizable, and suitable for patients ineligible for intensive systemic chemotherapy, including frail or elderly individuals.

Safety profiles across modalities remain manageable, with TAE and TACE demonstrating low (<5%) rates of severe adverse events, including hepatic abscess, biliary injury, and post-embolization syndrome. During VDA administration, transient hypertension or QT prolongation may occur, underscoring the need for cardiovascular monitoring. Non-invasive response assessment using perfusion CT, contrast-enhanced ultrasound, or dynamic MRI provides real-time evaluation of vascular shutdown and may guide timing of subsequent treatment cycles. The incorporation of radiologic biomarkers—such as perfusion index or vessel density—may further improve patient selection, dose optimization, and therapeutic monitoring as these approaches advance toward clinical validation.

Future Perspectives

The convergence of interventional oncology, vascular biology, and drug-delivery innovation is reshaping therapeutic possibilities for gastric cancer. Locoregional vascular-targeted therapy offers a strategic interface between systemic treatment and procedural interventions, enabling high intratumoral drug accumulation while limiting systemic exposure. Emerging evidence suggests that combining vascular disruption with immune checkpoint inhibitors or VEGFR-based therapy may enhance antitumor immunity through hypoxia-driven antigen release, vascular remodeling, and increased immune cell infiltration [22-24]. Parallel advances in nanotechnology—including liposomal vascular-disrupting agents (VDAs), polymeric embolic microspheres, and smart stimuli-responsive carriers—enable controlled, spatially restricted delivery and selective vascular occlusion. Future clinical development should prioritize early-phase trials evaluating endoscopic or arterial delivery of VDAs, supported by quantitative pharmacodynamic imaging such as perfusion CT or contrast-enhanced ultrasound. Identifying predictive biomarkers (e.g., VEGFR2 expression, circulating endothelial cells, HIF-1α signatures) will be critical for refining patient selection and guiding treatment personalization.

Discussions

Despite advances in targeted therapy and immunotherapy, treatment outcomes for advanced gastric cancer (GC) remain limited, reinforcing the need for novel therapeutic strategies. Systemic anti-angiogenic agents have demonstrated clinical relevance by targeting tumor vasculature; however, modest response durability and treatment-related toxicities indicate that systemic delivery alone is insufficient to overcome the structural complexity and adaptive biology of the gastric tumor microenvironment. Hypoxia-driven compensatory signaling, immune exclusion, and stromal activation contribute to therapeutic resistance, underscoring unmet clinical needs.

Locoregional vascular-targeted delivery has emerged as a promising strategy to enhance drug bioavailability while minimizing systemic exposure. Direct intratumoral or peritumoral administration enables high local drug concentration and may remodel the immune microenvironment by increasing antigen release and promoting immune infiltration. This creates a mechanistic basis for synergy with checkpoint blockade and VEGF-pathway inhibition. Additionally, the anatomical accessibility of the stomach supports integration of interventional technologies, including transarterial delivery, chemoembolization, and endoscopic ultrasound-guided injection.

Future work should optimize delivery parameters, incorporate perfusion-based imaging for response assessment, and establish biomarkers predictive of vascular response. Ultimately, combining locoregional vascular-targeted therapy with systemic treatment modalities may enable a transition toward precision-guided, multimodal therapy and improve clinical outcomes in advanced GC.

Conclusions

Vascular-targeted therapy represents a promising therapeutic direction in gastric cancer. While systemic anti-angiogenic agents such as ramucirumab have validated the tumor vasculature as an actionable target, their benefit is constrained by adaptive resistance mechanisms and dose-limiting toxicity. VDAs provide a mechanistically distinct approach capable of inducing rapid vascular collapse; however, their effective translation to gastric cancer will depend on delivery strategies that maximize tumor exposure while minimizing cardiovascular and systemic risk.

Existing interventional platforms—including transarterial embolization (TAE), transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and endoscopic ultrasound-guided fine-needle injection—already provide clinical infrastructure to support implementation. Integrating locoregional vascular-targeted therapy with systemic immunotherapy or anti-angiogenic treatment may enable a shift toward precision-guided multimodal care for advanced disease. Prospective trials are now essential to define safety, efficacy, and optimal therapeutic sequencing within the evolving treatment landscape.

Conflict of Interest

The authors have no conflicts of interest to declare and agreed to the published version of the manuscript.

Author Contributions

JYS conceived and designed the study, conducted all experiments and data analyses, interpreted the results, and wrote the entire manuscript. The author reviewed and approved the final version of the manuscript.

References

1. Huang J, Lucero-Prisno DE, 3rd, Zhang L, Xu W, Wong SH, Ng SC, Wong MCS: Updated epidemiology of gastrointestinal cancers in East Asia. Nat Rev Gastroenterol Hepatol 2023, 20(5):271-287.
2. Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, Committee EG: Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016, 27(suppl 5):v38-v49.
3. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010, 376(9742):687-697.
4. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A et al: First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021, 398(10294):27-40.
5. Jain RK: Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 2014, 26(5):605-622.
6. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014, 15(11):1224-1235.
7. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014, 383(9911):31-39.
8. Li J, Qin S, Xu J, Xiong J, Wu C, Bai Y, Liu W, Tong J, Liu Y, Xu R et al: Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction. J Clin Oncol 2016, 34(13):1448-1454.
9. Hartwich J, Orr WS, Ng CY, Spence Y, Morton C, Davidoff AM: HIF-1alpha activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts. J Pediatr Surg 2013, 48(1):39-46.
10. Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L: Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023, 8(1):198.
11. Bergers G, Hanahan D: Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008, 8(8):592-603.
12. Nagaiah G, Remick SC: Combretastatin A4 phosphate: a novel vascular disrupting agent. Future Oncol 2010, 6(8):1219-1228.
13. Vincent L, Kermani P, Young LM, Cheng J, Zhang F, Shido K, Lam G, Bompais-Vincent H, Zhu Z, Hicklin DJ et al: Combretastatin A4 phosphate induces rapid regression of tumor neovessels and growth through interference with vascular endothelial-cadherin signaling. J Clin Invest 2005, 115(11):2992-3006.
14. Wu XY, Ma W, Gurung K, Guo CH: Mechanisms of tumor resistance to small-molecule vascular disrupting agents: treatment and rationale of combination therapy. J Formos Med Assoc 2013, 112(3):115-124.
15. Rustin GJ, Shreeves G, Nathan PD, Gaya A, Ganesan TS, Wang D, Boxall J, Poupard L, Chaplin DJ, Stratford MR et al: A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer. Br J Cancer 2010, 102(9):1355-1360.
16. Park S, Shin JH, Gwon DI, Kim HJ, Sung KB, Yoon HK, Ko GY, Ko HK: Transcatheter Arterial Embolization for Gastrointestinal Bleeding Associated with Gastric Carcinoma: Prognostic Factors Predicting Successful Hemostasis and Survival. J Vasc Interv Radiol 2017, 28(7):1012-1021.
17. Minici R, Guzzardi G, Venturini M, Fontana F, Coppola A, Spinetta M, Piacentino F, Pingitore A, Serra R, Costa D et al: Transcatheter Arterial Embolization (TAE) of Cancer-Related Bleeding. Medicina (Kaunas) 2023, 59(7).
18. Vogl TJ, Gruber-Rouh T, Eichler K, Nour-Eldin NE, Trojan J, Zangos S, Naguib NN: Repetitive transarterial chemoembolization (TACE) of liver metastases from gastric cancer: local control and survival results. Eur J Radiol 2013, 82(2):258-263.
19. Wang K, Zhang X, Wei J, Xu Y, Liu Q, Xie J, Yuan L, Sun Z, Tan S, Zhang L et al: Hepatic Arterial Infusion Oxaliplatin Plus Oral S-1 Chemotherapy in Gastric Cancer with Unresectable Liver Metastases: A Case Series and Literature Review. Cancer Manag Res 2020, 12:863-870.
20. Jung YS, Koo DH, Yang JY, Lee HY, Park JH, Park JH: Peri-tumor administration of 5-fluorouracil sol-gel using a hollow microneedle for treatment of gastric cancer. Drug Deliv 2018, 25(1):872-879.
21. Kim NH, Park JH, Koo DH, Jung YS, Yang JY, Lee HY: A Pilot Study of Peritumor Administration of 5-FU for Preventing Bleeding in Advanced Gastric Cancer. Korean J Gastroenterol 2022, 80(6):273-280.
22. Lamplugh Z, Fan Y: Vascular Microenvironment, Tumor Immunity and Immunotherapy. Front Immunol 2021, 12:811485.
23. D'Alessio A, Rimassa L: A new standard for HCC: The high stakes of TACE-immunotherapy combinations. Med 2025, 6(3):100635.
24. Kudo M: Immune Checkpoint Inhibitor plus Anti-VEGF/TKI Combined with Transarterial Chemoembolization in Locally Advanced Nonmetastatic Hepatocellular Carcinoma: Real-World Treatment Strategy Based on Phase 3 Clinical Trial Results. Liver Cancer 2025, 14(3):241-247.