What are the pre-clinical and clinical results of combination of immunotherapy with cryoablation for breast cancer?

The combination of cryoablation and immunotherapy has emerged as a promising strategy in breast cancer, employing the immunogenic effects of locoregional tumor destruction to enhance systemic anti-tumor immunity. Cryoablation induces tumor cell death through repeated freeze–thaw cycles, resulting in cellular membrane disruption, osmotic injury, and apoptosis. Unlike thermal ablation techniques, cryoablation preserves tumor antigen integrity, allowing the release of intact tumor neoantigens into the tumor microenvironment [1,2]. This promotes dendritic cell recruitment and antigen presentation, effectively transforming the ablated tumor into an in situ vaccine. Pre-clinical breast cancer models demonstrate that cryoablation increases tumor-specific CD8+ cytotoxic T-cell activation, enhances interferon-γ signaling, and improves immune cell infiltration within the tumor microenvironment [3,4].

Despite these immunostimulatory effects, cryoablation alone is often insufficient to generate durable systemic immunity. Post-ablation immune responses may be limited by upregulation of immune checkpoint pathways such as PD-1/PD-L1 and CTLA-4, as well as expansion of regulatory T cells and other immunosuppressive cell populations [5]. These findings provide a strong mechanistic rationale for combining cryoablation with immune checkpoint inhibitors to sustain and amplify ablation-induced immune priming.

Pre-clinical studies consistently demonstrate synergistic anti-tumor effects with combination therapy. In murine breast cancer models, the addition of immune checkpoint blockade following cryoablation results in enhanced tumor regression, delayed growth of distant untreated tumors, and improved survival compared with either modality alone [6,7]. These findings support the induction of an abscopal effect, in which localized cryoablation generates systemic immune responses when paired with immunotherapy.

Early clinical evidence supports these mechanistic observations. Pilot studies in patients with early-stage and metastatic breast cancer have shown that cryoablation induces measurable systemic immune activation, including increased circulating tumor-specific T cells and favorable cytokine shifts [8]. When combined with immune checkpoint inhibitors, early-phase clinical trials and translational studies suggest enhanced immune infiltration and improved pathologic responses without significant increases in procedure-related toxicity [9]. The potential benefit appears particularly relevant in triple-negative breast cancer, a subtype characterized by higher immunogenicity and limited targeted treatment options [10].

In summary, cryoablation functions as an in situ tumor vaccine that enhances antigen release and immune priming, while immunotherapy overcomes adaptive immune resistance mechanisms. Although existing data suggest synergistic benefit, prospective randomized trials are needed to define optimal patient selection, treatment sequencing, and long-term oncologic outcomes [11].