Anti-PD1 blockade as first-line therapy in early-stage unfavorable CHL shows distinct differences in clinical and histologic response. CHL exhibits rare malignant HRS cells in a TME enriched for inflammatory cells, particularly CD4⁺LAG3⁺ Tr1s, PDL1⁺ TAMs, and fewer CD8⁺ cytotoxic T cells (left). Biopsies following first-line anti–PD1-based therapy in early-stage unfavorable CHL patients show dramatic decrease in CD30⁺PDL1⁺ HRS cells along with depletion of Tr1 cells and PDL1⁺ TAMs, especially in the vicinity of HRS cells, with no expansion of CD8⁺ cytotoxic T cells (right). These findings underscore significant differences in the TME composition of pre- and posttreatment CHL and favor withdrawal of survival factors rather than cytotoxic immune responses as the most likely mechanism of action in first-line immune checkpoint blockade.