Understanding why some patients with melanoma respond to immunotherapy while others do not has remained a critical challenge for precision medicine. A new study investigates immune time-resolved Förster resonance energy transfer (iFRET) as a novel diagnostic tool to predict immunotherapy outcomes in Stage II melanoma. This research provides groundbreaking insights into the tumor immune microenvironment (TiME) and its dynamic response to treatment.
The study evaluated tissue samples from a Phase II trial of neoadjuvant oncolytic virus therapy prior to surgery. Using iFRET technology, researchers assessed PD-L1:PD-1 interactions, a critical immune checkpoint mechanism, before and after treatment. Results showed that tumors responding to therapy exhibited significant increases in iFRET efficiency, highlighting active immune engagement. In contrast, nonresponsive tumors displayed either reduced checkpoint activity or no immune stimulation, signaling a lack of therapeutic impact.
Notably, traditional biomarkers, such as PD-L1 expression and T-cell phenotyping, failed to reliably predict therapy response. Significant variability was observed between patients and within tumor regions, further underscoring the need for functional biomarkers like iFRET.
The study also revealed a strong correlation between the phenotype of tumor-associated macrophages and response to therapy. Complete responders demonstrated both a high presence of PD-L1:PD-1 interactions and innate immune activity, suggesting macrophages play a critical role in orchestrating the immune response.
These findings position iFRET as a promising diagnostic tool for better understanding immune checkpoint function and tailoring treatments to individual patient profiles. The research underscores the importance of integrating functional biomarkers into clinical trials, potentially transforming how melanoma therapies are personalized in the future.
By addressing the variability in immune profiles and immune checkpoint engagement, this study highlights an exciting path forward in precision immunotherapy, aiming to improve outcomes for melanoma patients. Further exploration of these biomarkers in larger trials are warranted.
Reference: Kirane AR et al. Toward Functional Biomarkers of Response to Neoadjuvant Oncolytic Virus in Stage II Melanoma: Immune-Förster Resonance Energy Transfer and the Dynamic Tumor Immune Microenvironment. JCO OA. 2025;2.
Anaya Malik | AMJ
