Radiofrequency ablation: mechanisms and clinical applications

Abstract

Radiofrequency ablation (RFA), a form of thermal ablation, employs localized heat to induce protein denaturation in tissue cells, resulting in cell death. It has emerged as a viable treatment option for patients who are ineligible for surgery in various diseases, particularly liver cancer and other tumor-related conditions. In addition to directly eliminating tumor cells, RFA also induces alterations in the infiltrating cells within the tumor microenvironment (TME), which can significantly impact treatment outcomes. Moreover, incomplete RFA (iRFA) may lead to tumor recurrence and metastasis. The current challenge is to enhance the efficacy of RFA by elucidating its underlying mechanisms. This review discusses the clinical applications of RFA in treating various diseases and the mechanisms that contribute to the survival and invasion of tumor cells following iRFA, including the roles of heat shock proteins, hypoxia, and autophagy. Additionally, we analyze‌ the changes occurring in infiltrating cells within the TME after iRFA. Finally, we provide a comprehensive summary of clinical trials involving RFA in conjunction with other treatment modalities in the field of cancer therapy, aiming to offer novel insights and references for improving the effectiveness of RFA.

Keywords: colorectal cancer liver metastases; combination therapies; hepatocellular carcinoma; incomplete radiofrequency ablation; tumor microenvironment.

FIGURE 1

Therapeutic principles of RFA and main causes of iRFA. (A) Complete radiofrequency ablation: the theoretical basis for how RFA eliminates tumors: by inserting a radiofrequency needle into the tumor tissue and powering it on, the current causes ions in the tissue to vibrate and rub rapidly, generating heat. When the temperature reaches 60°C, proteins within the cells denature, causing cancer cells to dehydrate and degenerate, leading to coagulative necrosis and ultimately achieving the goal of destroying cancer cells. B: Insufficient Ablation: the causes of insufficient ablation: (1) large size and irregular shape; (2) heat sink effect; (3) adjacent to organs/surface.

FIGURE 2

Alterations in tumor cell characteristics and their underlying regulatory mechanism following iRFA. In 2004, HSPs were first proposed to be associated with tumor recurrence and metastasis after iRFA. Subsequently, related research was carried out continuously. HIF‐VEGF, IL‐6/HGF/c‐MET/STAT3 signal axis, and EMT have also been suggested to be involved in tumor recurrence after iRFA. The increase in the dryness of tumor cells fuels the progression of residual tumor cells. Noncoding RNA and epigenetic modifications, as well as autophagy, also drive tumor progression. CQ, chloroquine; HCQ, hydroxychloroquine.

FIGURE 3

Mechanism of antitumor immune TME formation after RFA. RFA can activate the immune response and promote the infiltration of various relevant cells, including APCs (e.g., DCs), tumor‐killing cells (e.g., CD8+ T and NK cells), and “danger” signals (e.g., HSP70), to exert antitumor efficacy.

FIGURE 4

Mechanisms underlying the formation of an immunosuppressive microenvironment following iRFA. (A) Exhaustion markers (such as PD‐1, Tim‐3, CD160, and CD244) on TILs were upregulated after iRFA, ultimately resulting in immune evasion and malignant progression. (B) MDSCs are involved in inhibiting the antitumor immune response of TILs. (C) Elevated levels of histones in the peripheral blood stimulate neutrophils to produce cytokines, which in turn leads to the release of MPO. (D) The CD56^brightCD16‐ NK cell suppresses STAT5 expression and upregulates VEGFA, thereby promoting angiogenesis. (E) M2‐like polarization of macrophages is involved in the formation of a suppressive tumor immune microenvironment. (F) Reduced maturation of DC cells participate in the attenuation of antigen‐presenting functions. POSTN, periostin; MPO, myeloperoxidase; MCP‐1, monocyte chemotactic protein‐1.