Immunotherapy agents are now entering the clinic in a wide array of malignancies and have provided a valuable addition to the therapeutic armamentarium. These agents enhance the global immune response by modulating the tumor microenvironment but can lead to unconventional patterns of response, challenging the conceptual framework that imaging is a robust surrogate for therapeutic efficacy. There is also increasing evidence that an effective anti-tumor response requires a systemic immune

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... (SIR) in primary and secondary lymphoid tissues. However, an enhanced SIR can lead to disruption of immunologic hemostasis in healthy tissues, causing adverse events. Better understanding of the complex interplay between tumoral and systemic immune response has been provided through tissue and liquid biopsy. However, the applicability of these methods is constrained by the biological, spatial, and temporal heterogeneity of the processes involved. There is a growing interest in molecular imaging of cell-specific lineage markers of the immune system using biomolecules. However, the ongoing role of the more widely available 18F-fluorodeoxyglucose positron-emission tomography with computed tomography (FDG PET/CT) for response assessment is being recognized through ongoing refinement of interpretative guidelines and emerging evidence. These non-invasive methods provide insights into the biologic basis of the global immune response to maximize potential therapeutic benefit. In this review, we aim to provide an overview of the current status of FDG PET/CT in the monitoring of tumoral and systemic immune response. In a companion review, the role of other imaging probes that might complement FDG PET/CT will be discussed.