Tumor mass dormancy - a potential driver of long-term persistent melanoma after immunotherapy?

Introduction - Persistent residual lesions represent a common yet ambiguous outcome in melanoma patients treated with immune checkpoint inhibitors (ICIs). These lesions can reflect either (i) disease eradication with fibrosis and necrosis, or multiple modes of tumor dormancy, including (ii) residual disease characterized by cellular dormancy or quiescence, and (iii) macroscopic tumor mass dormancy, in which overall stability emerges from a dynamic balance between tumor proliferation and loss. Because these lesions are infrequently biopsied, the biological mechanisms that sustain these forms of dormancy remain poorly defined. This study aimed to characterize the cellular and microenvironmental states underlying persistent residual disease following ICI therapy. Methods - We performed multi-omics spatial profiling on persistent residual lesions resected from six ICI-treated melanoma patients. For comparison, we included lymph node metastases from patients who progressed after ICIs. Results - In 4 of 6 patients, persistent residual lesions consisted largely of immune cells and scar tissue, suggesting that the PET signal may arise primarily from non-tumor components rather than residual viable tumor. In contrast, one patient with a large residual lymph node lesion harbored viable, proliferating tumor cells at levels comparable to - or exceeding - those in lymph node lesions from patients with active clinical progression after ICI therapy. Extensive cytotoxic T-cell infiltration and high levels of programmed cell death were observed within this lesion. Although some tumor cells expressed cellular dormancy-associated markers (e.g., p27), this was not the dominant tumor state. Strikingly, in another patient, a persistent residual lesion that was pathologically negative for tumor cells by H&E contained discrete nests of tumor cells identified by multiplex IF, with approximately half of them proliferating in close proximity to immune cells. Conclusion - Together, these findings demonstrate that post-ICI residual disease can arise from persistent, viable tumor cells and that the phenotype is more consistent with tumor mass dormancy rather than the classical cellular dormancy concept. Furthermore, the persistent residual lesion can harbor viable and proliferative tumor cells despite appearing clinically stable, underscoring that such lesions may act as reservoirs with potential for late progression. This dormancy-like state has important implications for patient monitoring, clinical interpretation of stability, and long-term management following ICI therapy.