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Simple Summary: Radiofrequency ablation (RFA), when used for the treatment of pulmonary metastases, results in the generation of tumor-specific neo-antigens that may prime an immune response of the remaining metastases. Under these circumstances, the immune system may become responsible for the widespread attack of the remaining neoplasia. Immune checkpoint interactions are thought to limit this response. A platform that enables the precise measurement of immune checkpoint interactions and stratifies patients for immunotherapies, alongside radiofrequency ablation, may be a potent method for enhancing response rates in patients with metastases. To determine the immune mechanism triggered by RFA, leading to this abscopal effect, we have exploited our imaging platform that quantifies the spatio-functional states of biomarkers rather than their expression level. This platform has been tested on patients treated by RFA on lung metastases from colorectal cancer. For the first time, we have demonstrated how this platform could be used for determining the tumor and immune cell interactions in RFA patients. Background: Cases of the spontaneous regression of multiple pulmonary metastases, after radiofrequency ablation (RFA), of a single lung metastasis, have been documented to be mediated by the immune system. The interaction of immune checkpoints, e.g., PD-1/PD-L1 and CTLA-4/CD80, may explain this phenomenon. The purpose of this study is to identify and quantify immune mechanisms triggered by RFA of pulmonary metastases originating from colorectal cancer. Methods: We used two-site time-resolved Förster resonance energy transfer as determined by frequency-domain FLIM (iFRET) for the quantification of receptor–ligand interactions. iFRET provides a method by which immune checkpoint interaction states can be quantified in a spatiotemporal manner. The same patient sections were used for assessment of ligand–receptor interaction and intratumoral T-cell labeling. Conclusion: The checkpoint interaction states quantified by iFRET did not correlate with ligand expression. We show that immune checkpoint ligand expression as a predictive biomarker may be unsuitable as it does not confirm checkpoint interactions. In pre-RFA-treated metastases, there was a significant and negative correlation between PD-1/PD-L1 interaction state and intratumoral CD3+ and CD8+ density. The negative correlation of CD8+ and interactive states of PD-1/PD-L1 can be used to assess the state of immune suppression in RFA-treated patients. [ABSTRACT FROM AUTHOR]