Researchers from Sun Yat-sen University Cancer Center and collaborating institutions have constructed what they describe as the first systematic pan-cancer single-cell atlas of tumor angiogenesis. The team analyzed approximately 1.24 million individual cells from 381 tumor samples representing 13 common cancer types, including breast, colorectal, gastric, liver, and lung cancers. By examining gene activity cell by cell, the investigators mapped the cellular networks that promote abnormal blood-vessel formation across diverse malignancies.

Angiogenesis is essential for tumors that outgrow the oxygen and nutrients available through diffusion. Cancer-associated blood vessels are typically disorganized, leaky, and structurally unstable, creating regions of hypoxia that can further alter tumor and stromal cells. Drugs such as bevacizumab and other anti-VEGFR therapies interfere with this process by blocking signals that stimulate endothelial cells, the cells lining blood vessels. Although these treatments can slow disease in some patients, their benefits are often temporary, and resistance is common.

The new atlas revealed that pericytes and the molecules they release are strongly associated with angiogenic activity across cancer types. Pericytes normally wrap around microvessels and help regulate vascular stability, permeability, and blood flow. Within tumors, however, these cells can be reprogrammed by abnormal signaling and a hostile microenvironment. The researchers identified a distinct population known as MCAM-positive immature pericytes, or MCAM+ imPCs, which emerged as a major source of two potent pro-angiogenic factors: placental growth factor, known as PGF, and angiopoietin-2, or ANGPT2.

PGF and ANGPT2 can support blood-vessel growth through pathways that are not fully dependent on VEGF. ANGPT2, in particular, can destabilize existing vessels and make them more responsive to additional angiogenic signals, while PGF can promote endothelial-cell activation and vascular remodeling. The study indicates that MCAM+ imPCs are shaped by dysregulated Notch signaling and hypoxic stress in the tumor microenvironment. In effect, these cells appear to function as an alternative angiogenic engine, allowing tumors to maintain or restore vascular growth despite VEGF pathway inhibition.

Laboratory experiments provided evidence that the MCAM+ imPC population is not merely correlated with treatment failure but actively contributes to it. In cell-based and animal studies, the pericytes stimulated alternative vascular responses and reduced the effectiveness of anti-VEGFR treatment. Clinical analyses reinforced the finding. Among patients with ovarian cancer, urothelial cancer, and glioblastoma who received bevacizumab, higher levels of MCAM+ imPCs were associated with shorter overall survival and progression-free survival. These observations suggest that the abundance of these cells could eventually serve as a biomarker for identifying tumors likely to resist anti-angiogenic therapy.

The investigators then tested a strategy designed to eliminate the cellular source of the resistance signals. They developed an MCAM-targeting antibody-drug conjugate, or ADC, capable of recognizing the MCAM protein on the surface of the immature pericytes and delivering a cytotoxic payload. Rather than blocking a single secreted factor, the approach is intended to remove the pro-angiogenic cell population responsible for producing PGF and ANGPT2. This distinction could be important because tumor cells and stromal cells often compensate when one signaling molecule is inhibited.

When the MCAM ADC was combined with anti-VEGFR therapy, the treatment produced stronger suppression of angiogenesis and tumor growth than either treatment alone in mouse models of breast, renal, and lung cancers. The researchers describe the approach as dual endothelial-cell and pericyte inhibition. Anti-VEGFR drugs primarily disrupt signaling to endothelial cells, while the ADC targets the pericyte compartment that supports alternative vessel formation. By attacking both parts of the tumor vascular system, the combination may make it more difficult for tumors to bypass treatment.

Safety studies in the experimental models also produced encouraging results. The MCAM ADC did not cause significant changes in body weight, blood-cell counts, liver function, kidney function, or blood-brain barrier integrity. These findings do not establish clinical safety, but they provide preliminary support for further development. A humanized version of the therapy, AMT-253, is already being evaluated in a first-in-human Phase I trial listed under ClinicalTrials.gov identifier NCT05906862. Early-stage trials are primarily designed to assess safety, dosing, and tolerability rather than to prove effectiveness.

The study reframes anti-angiogenic resistance as a problem involving more than endothelial cells and VEGF. It suggests that the tumor microenvironment contains specialized support cells capable of preserving vascular growth through parallel molecular routes. If the findings are confirmed in larger clinical studies, MCAM+ immature pericytes could become both a therapeutic target and a predictive marker for anti-angiogenic treatment. The researchers say their pan-cancer atlas and dual-targeting strategy may help guide more durable vascular therapies, although the clinical value of MCAM ADCs will depend on results from ongoing human trials.

The work was led by Professors Xu Ruihua, Liu Zexian, and Luo Huiyan of Sun Yat-sen University Cancer Center, who served as co-corresponding authors. Dr. Zheng Yongqiang, Dr. Sun Hui, Dr. Fu Zhe, Dr. Chen Haojie, and Dr. Cai Guangyao were listed as co-first authors. The research was supported by Chinese national, provincial, and institutional funding programs, including the National Key R&D Program of China, the National Natural Science Foundation of China, and programs supporting young investigators and postdoctoral researchers.

Subject of Research: Tumor angiogenesis, anti-angiogenic therapy resistance, MCAM-positive immature pericytes, and MCAM-targeting antibody-drug conjugates.

Web References: https://doi.org/10.1016/j.scib.2026.06.022; ClinicalTrials.gov identifier NCT05906862

References: Science Bulletin, DOI: 10.1016/j.scib.2026.06.022

Image Credits: © Science Bulletin / Authors

Keywords: cancer research, tumor angiogenesis, pericytes, VEGF, anti-angiogenic therapy, bevacizumab, MCAM, MCAM ADC, AMT-253, PGF, ANGPT2, cancer drug resistance, single-cell analysis, tumor microenvironment, antibody-drug conjugate

Tumors are notorious for their aberrant vascular structures — chaotic, leaky, and dysfunctional blood vessels that hinder effective drug delivery and oxygenation. This hostile microenvironment not only limits the success of chemotherapeutic and immunotherapeutic regimens but also fuels tumor progression and resistance. Addressing these issues, the study explores the innovative use of microbubbles, minuscule gas-filled spheres, in conjunction with ultrasound waves, to induce cavitation — the rapid oscillation and collapse of microbubbles — thereby mechanically influencing the tumor vasculature.

The researchers employed a rabbit VX2 tumor model, a well-established preclinical system that closely mimics the aggressive and vascular characteristics of human cancers. By carefully calibrating ultrasound parameters to stimulate microbubble cavitation without causing significant tissue damage, they observed a marked improvement in tumor blood flow. Enhanced perfusion was noted immediately after treatment and persisted for a duration that has critical implications for therapeutic windows.

At the core of this advancement lies the concept of vascular normalization — a therapeutic strategy aimed at restoring the structure and function of tumor blood vessels toward a more organized and efficient state. The study demonstrates that ultrasound-stimulated cavitation promotes this normalization process, reversing the chaotic architecture characteristic of malignant vasculature. Improved vessel integrity leads to better delivery of oxygen and nutrients, thereby alleviating hypoxic conditions that often drive tumor aggressiveness and therapy resistance.

Detailed histological analyses revealed that post-treatment tumors exhibited significantly reduced vessel permeability and increased pericyte coverage, indicative of stabilized and mature blood vessels. This contrasts sharply with the pre-treatment state where vessels showed fragility and leakiness. Such stabilization is crucial not only for drug delivery but also for minimizing interstitial pressure within tumors, which often impedes therapeutic agent penetration.

The mechanistic insights provided by the study suggest that the mechanical forces exerted by cavitating microbubbles stimulate endothelial cells lining the blood vessels, triggering signaling pathways conducive to vessel remodeling and repair. This biomechanical interaction paves the way for non-invasive modulation of tumor biology, harnessing physical forces to invoke biological responses favorable to treatment.

Clinically, these findings hold promise for synergistic cancer therapy approaches. Combining ultrasound-stimulated microbubble cavitation with chemotherapy, radiotherapy, or immunotherapy could overcome barriers posed by the dysfunctional tumor vasculature. Enhanced perfusion not only facilitates drug access but may also improve immune cell infiltration, amplifying anti-tumor immunity.

Importantly, the safety profile of this approach appears favorable. The study meticulously optimized ultrasound parameters to avoid tissue damage, with no significant adverse effects observed in normal surrounding tissues. This non-destructive modulation contrasts with traditional therapeutic methods that often carry high toxicity and collateral damage risks.

Furthermore, the ultrasound and microbubble strategy offers a highly controllable and targeted modality. Ultrasound can be precisely focused on tumor regions, allowing spatial and temporal control over treatment effects. Microbubbles, inherently confined to the vasculature, act as localized agents, minimizing systemic exposure and side effects.

The implications extend beyond oncology. The principles demonstrated here could be translated to other pathological conditions characterized by abnormal vasculature, such as cardiovascular diseases and wound healing disorders. Modulating blood vessel function non-invasively through ultrasound-mediated cavitation could become a versatile tool in regenerative medicine.

The study also raises intriguing questions about the interplay between mechanical forces and cellular signaling in the tumor microenvironment. Future research may unravel new molecular targets activated by cavitation-induced stresses, opening avenues for combination therapies that exploit these newly uncovered pathways.

In summary, this trailblazing investigation charts a promising course for augmenting cancer treatment through physical modulation of tumor blood vessels. Ultrasound-stimulated microbubble cavitation emerges as a powerful, non-invasive technique to improve tumor perfusion, promote vascular normalization, and ultimately enhance the delivery and efficacy of anti-cancer therapies.

As the oncology field increasingly embraces innovative strategies that transcend conventional pharmacology, the integration of biomechanical approaches such as this could redefine therapeutic paradigms. Clinical translation will require meticulous validation, but the foundational evidence presented provides robust optimism for the future of cancer care.

This research, heralding a fusion of physics, biology, and medicine, exemplifies the cutting edge of translational science. It underscores the potential of harnessing ultrasonics and microbubbles not just as diagnostic tools but as dynamic instruments of therapeutic transformation.

With further refinement and validation, ultrasound-stimulated microbubble cavitation might soon become a standard adjunct in oncological protocols, enhancing patient outcomes in ways previously unattainable. The convergence of technology and biology continues to unlock new frontiers that hold promise for conquering some of the most formidable challenges in medicine.

Subject of Research: Ultrasound-stimulated microbubble cavitation and its effects on tumor perfusion and vascular normalization in cancer therapy.

Article Title: Ultrasound-Stimulated microbubble cavitation improved tumor perfusion and promoted tumor vascular normalization in a rabbit VX2 tumor model.

Article References:
Luo, T., Bai, L., Yao, L. et al. Ultrasound-Stimulated microbubble cavitation improved tumor perfusion and promoted tumor vascular normalization in a rabbit VX2 tumor model. Med Oncol 43, 89 (2026). https://doi.org/10.1007/s12032-025-03226-x

Image Credits: AI Generated

DOI: https://doi.org/10.1007/s12032-025-03226-x