Histotripsy-induced vascular remodeling in the tumor microenvironment enhances local and off-target intratumoral drug delivery
- 1Department of Cell Biology, Van Andel Institute; Grand Rapids, Michigan, USA
Abstract
Solid tumors are known to be refractory to treatment due to a poorly perfused microenvironment that blocks immune cell infiltration and effective drug delivery. Histotripsy is a non-invasive focused ultrasound modality that generates cavitation microbubbles to mechanically disrupt solid tumors, resulting in decreased hypoxia and stimulation of tumor-targeted adaptive immune responses. In this study, we aim to investigate whether post-histotripsy hypoxia reduction and cytotoxic immune cell infiltration are associated with normalization of tumor vasculature and enhanced perfusion. Structural analysis of both treated and contralateral off-target tumors following partial histotripsy revealed significant vascular remodeling, enhanced vascular integrity, and decreased vascular leakage indicative of vascular normalization in multiple in vivo models of melanoma, hepatocellular carcinoma, and pancreatic adenocarcinoma. These effects appeared antigen-specific, as no remodeling was observed in contralateral off-target tumors of discordant pathology. Mechanistically, CXCR3+CD8+ T cells played a role in mediating these vascular changes, as genetic knockout of CD8 and pharmacological antagonism of CXCR3 impaired both remodeling and normalization. Additionally, significant changes in endothelial CXCR4 and Angiopoietin-1 and -2 expressions were observed following histotripsy, indicating their potential involvement in promoting vascular normalization and remodeling. Significant vascular remodeling was accompanied by enhanced tumor perfusion and intratumoral delivery of chemotherapeutic agents and therapeutic monoclonal antibodies. These findings suggest that histotripsy not only creates a more favorable microenvironment for immunotherapy, but also optimizes drug delivery into solid tumors. Combinatorial approaches using histotripsy with chemotherapy or immunotherapy may be a novel therapeutic strategy to overcome current limitations of conventional solid tumor therapies.
Related
- Evolution of vascular normalization strategies: from anti-angiogenesis to remodeling the tumor microenvironment
- Oncolytic reovirus: tumor-microenvironment remodeling, engineering constraints, and translational strategies
- Remodeling of the brain immune microenvironment in Alzheimer’s disease: interactions among microglia, astrocytes, complement, and the neurovascular unit
- Smooth muscle DDIT4 exacerbates vascular remodeling in atherosclerosis and vascular injury by impairing PDC activity
- Tumor cell-intrinsic mtDNA instability drives cGAS-dependent temporal remodeling of the melanoma immune microenvironment
BibTeX
@misc{queen2026histotripsyinduced,
title = {{Histotripsy-induced vascular remodeling in the tumor microenvironment enhances local and off-target intratumoral drug delivery}},
author = {H. Queen and B. Song and H. Kim and R. McGinnis and J. Liu and A. Sanogo and K. Buglak and C. Karanam and A. Bontrager and T. Worlikar and Z. Xu and A. Ganguly and C. S. Cho},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752667},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752667v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Histotripsy-induced vascular remodeling in the tumor microenvironment enhances local and off-target intratumoral drug delivery
AU - H. Queen
AU - B. Song
AU - H. Kim
AU - R. McGinnis
AU - J. Liu
AU - A. Sanogo
AU - K. Buglak
AU - C. Karanam
AU - A. Bontrager
AU - T. Worlikar
AU - Z. Xu
AU - A. Ganguly
AU - C. S. Cho
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752667
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752667v1
AB - Solid tumors are known to be refractory to treatment due to a poorly perfused microenvironment that blocks immune cell infiltration and effective drug delivery. Histotripsy is a non-invasive focused ultrasound modality that generates cavitation microbubbles to mechanically disrupt solid tumors, resulting in decreased hypoxia and stimulation of tumor-targeted adaptive immune responses. In this study, we aim to investigate whether post-histotripsy hypoxia reduction and cytotoxic immune cell infiltration are associated with normalization of tumor vasculature and enhanced perfusion. Structural analysis of both treated and contralateral off-target tumors following partial histotripsy revealed significant vascular remodeling, enhanced vascular integrity, and decreased vascular leakage indicative of vascular normalization in multiple in vivo models of melanoma, hepatocellular carcinoma, and pancreatic adenocarcinoma. These effects appeared antigen-specific, as no remodeling was observed in contralateral off-target tumors of discordant pathology. Mechanistically, CXCR3+CD8+ T cells played a role in mediating these vascular changes, as genetic knockout of CD8 and pharmacological antagonism of CXCR3 impaired both remodeling and normalization. Additionally, significant changes in endothelial CXCR4 and Angiopoietin-1 and -2 expressions were observed following histotripsy, indicating their potential involvement in promoting vascular normalization and remodeling. Significant vascular remodeling was accompanied by enhanced tumor perfusion and intratumoral delivery of chemotherapeutic agents and therapeutic monoclonal antibodies. These findings suggest that histotripsy not only creates a more favorable microenvironment for immunotherapy, but also optimizes drug delivery into solid tumors. Combinatorial approaches using histotripsy with chemotherapy or immunotherapy may be a novel therapeutic strategy to overcome current limitations of conventional solid tumor therapies.
ER -