VEGFR2 blockade converts thermally ablative focused ultrasound into a potent driver of T cell-dependent anti-tumor immunity

Abstract

Thermally ablative focused ultrasound (TFUS) can induce favorable immune signatures in solid tumors but rarely generates durable systemic immunity or enhances checkpoint inhibition. We tested whether combining TFUS with aVEGFR2, which normalizes tumor vasculature and remodels immune cell composition, triggers T cell-dependent immunity and synergizes with checkpoint inhibition. Subtotal TFUS ([~]40% volumetric ablation fraction, matching clinical trial results) was applied to EMT6 tumors in aVEGFR2-treated BALB/c mice. In EMT6 tumors, TFUS or aVEGFR2 alone had no effect on tumor growth, but their combination eradicated 50% of tumors and drove 83% rechallenge rejection, with CD4/CD8 depletion confirming that tumor eradication and rechallenge rejection were T cell-dependent. TFUS + aPD1 yielded modest benefit, whereas triple therapy (TFUS + aVEGFR2 + aPD1) cured 81% of mice and induced durable, T cell-mediated immunity. Thus, VEGFR2 blockade converts clinically relevant TFUS into a potent systemic immunotherapy and, with the addition of checkpoint inhibition, offers a rational approach to combining already-approved therapies for the treatment of solid tumors.