Abstract
Immune checkpoint inhibitors (ICIs) are designed to reinvigorate antitumor immune responses by interrupting inhibitory signaling pathways and promoting the immune-mediated elimination of malignant cells. Although ICI therapy has transformed the landscape of cancer treatment, only a subset of patients achieve a complete response. Focused ultrasound (FUS) is a noninvasive, nonionizing, deep penetrating focal therapy that has great potential to improve the efficacy of ICIs in solid tumors. Five FUS modalities have been incorporated with ICIs to explore their antitumor effects in preclinical studies, namely, high-intensity focused ultrasound (HIFU) thermal ablation, HIFU hyperthermia, HIFU mechanical ablation, ultrasound-targeted microbubble destruction (UTMD), and sonodynamic therapy (SDT). The enhancement of the antitumor immune responses by these FUS modalities demonstrates the great promise of FUS as a transformative cancer treatment modality to improve ICI therapy. Here, this review summarizes these emerging applications of FUS modalities in combination with ICIs. It discusses each FUS modality, the experimental protocol for each combination strategy, the induced immune effects, and therapeutic outcomes.
Highlights
Immune checkpoint inhibitor (ICI) therapy has revolutionized the paradigm of cancer immunotherapy
These findings [13,14,15,16] suggest that high-intensity focused ultrasound (HIFU) mechanical ablation alone, without the need for adjuvants, is sufficient to enhance ICI therapy for the treatment of cancers that are unresponsive to ICIs
Further development of the combination strategy requires a multidisciplinary approach with a proper choice of Focused ultrasound (FUS) parameters for particular tumors, a complete examination of the correlation between FUS parameters and antitumor immune effects, a thorough evaluation of the biological mechanisms for therapeutic outcome, and a good understanding of the clinical challenges in cancer immunotherapy
Summary
Immune checkpoint inhibitor (ICI) therapy has revolutionized the paradigm of cancer immunotherapy. HIFU thermal ablation has been reported to increase the release of damage-associated molecular patterns (DAMPs) and TAAs, promote DC maturation, increase tumor-infiltrating lymphocytes, and change circulating immunosuppressive cytokine levels [33], suggesting the potential to improve ICI efficacy for tumors that do not respond well to ICIs. The first study on therapeutic ultrasound-enhanced ICI therapy was reported in 2017 by Silvestrini et al [7]. The first study on therapeutic ultrasound-enhanced ICI therapy was reported in 2017 by Silvestrini et al [7] They explored whether HIFU thermal ablation could be effectively incorporated with ICIs to boost antitumor immune responses in murine breast cancer models. The subsequent HIFU thermal ablation released tumor antigens, inflammatory chemokines and cytokines, increased interferon stimulating genes, and altered the local macrophage phenotype These effects led to cross-presentation and cross-priming mediated by macrophages and DCs, resulting in an effective abscopal response. HIFU thermal ablation was followed by direct injection of nanoadjuvants into the ablated site and intravenous injection of anti-CTLA-4 antibody (αCTLA-4)
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