Although immunotherapy has revolutionized the entire cancer treatment landscape, small fractions of patients respond to immunotherapy. Early identification of responders may improve patient management during immunotherapy. In this study, we evaluated a PET approach for monitoring immunotherapy in lung cancer by imaging the upregulation of lymphocyte activation gene 3 (LAG-3)-expressing (LAG-3⁺) tumor-infiltrating lymphocytes (TILs). Methods: We synthesized a LAG-3-targeted molecular imaging probe, [⁶⁸Ga]Ga-NOTA-C25 and performed a series of in vitro and in vivo assays to test its specificity. Next, [⁶⁸Ga]Ga-NOTA-C25 PET was used to monitor immunotherapy in murine lung cancer-bearing mice and in humanized mouse models for assessing clinical translational potential, with confirmation by immunostaining and flow cytometry analysis. Results: [⁶⁸Ga]Ga-NOTA-C25 PET could noninvasively detect intertumoral differences in LAG-3⁺ TIL levels in different tumor models. Importantly, in Lewis lung carcinoma tumor models treated with an agonist of a stimulator of interferon genes, [⁶⁸Ga]Ga-NOTA-C25 PET also detected an immunophenotyping transition of the tumor from "cold" to "hot" before changes in tumor size. Meanwhile, animals carrying "hot" tumor showed more significant tumor inhibition and longer survival than those carrying "cold" tumor. [⁶⁸Ga]Ga-NOTA-C25 PET also showed markedly higher tumor uptake in immune system-humanized mice carrying human non-small cell lung cancer than immunodeficient models. Conclusion: [⁶⁸Ga]Ga-NOTA-C25 PET could be used to noninvasively monitor the early response to immunotherapy by imaging LAG-3⁺ TILs in lung cancer. [⁶⁸Ga]Ga-NOTA-C25 PET also exhibited excellent translational potential, with great significance for the precise management of lung cancer patients receiving immunotherapy.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	16
2	Cell Biology	1	1	16
3	Pathology	1	1	16
4	Cancer Cell Biology	1	1	16
5	Molecular Oncology	1	1	16

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