Noninvasive deciphering of the immunosuppressive tumor microenvironment and evaluation of MerTK inhibitor mediated reversal of ICB resistance via MerTK-targeted PET.

Immune checkpoint blockade (ICB) has demonstrated substantial clinical benefits in cancer treatment. However, many patients fail to achieve durable responses and eventually develop resistance. This study aimed to identify new strategies for predicting immunotherapy response and overcoming ICB resistance via PET imaging in tumor-bearing models. We used a MER proto-oncogene tyrosine kinase (MerTK) targeting radio-tracer, [68Ga]Ga-MerTKi, to noninvasively monitor MerTK expression level with PET/CT scanning in multiple murine cancer models. An ICB-resistant B16F10 melanoma tumor model was established, and we further verified that the combined treatment with MerTK inhibitor UNC2025 and anti-mouse PD-1 recombinant mAb effectively restored the ICB treatment efficacy. We first demonstrated that elevated MerTK expression is strongly correlated to [68Ga]Ga-MerTKi high uptake, poor response to ICB, and the subsequent development of resistance. We found that tumors with low MerTK expression responded well to immunotherapy, while for those with high MerTK expression did not. Importantly, [68Ga]Ga-MerTK PET predicted tumor sensitivity toward ICB therapy before treatment begins, making it a promising strategy to improve patient stratification and ICB treatment optimization. Moreover, the tracer allowed us to monitor MerTK expression level during treatment, which may provide guidance on treatment strategies down the road. Our findings indicate that [68Ga]Ga-MerTKi PET can potentially identify patients who may benefit from ICB therapy alone and who may need combination therapy. This observation supports the use of MerTK PET as a tool to guide more personalized treatment in cancer immunotherapy.