L19IL2 is a clinical-stage antibody-cytokine fusion protein that has been investigated for the treatment of various cancer types. Despite its promising antitumor activity, the precise mechanism of action is still not fully understood.

In this work, we employed a myc-driven B-cell lymphoma murine model to demonstrate that systemic administration of L19IL2 induced a robust CD8⁺ T cell-dependent tumor regression across multiple organs without expansion of regulatory T cells.

Following L19IL2 administration, intratumoral CD8⁺ T cells proliferated and acquired effector and memory phenotypes, associated with private clonal expansion and enhanced killing. Moreover, the spatial behavior of peritumoral CD8⁺ T cells studied by intravital microscopy demonstrated a rapid increase in tumor-directed motility and infiltration following L19IL2 administration.

These findings described the detailed mechanism of action of L19IL2 against B cell lymphoma and revealed for the first time the dynamic responses of peritumoral CD8⁺ T cells to targeted IL2 stimulation, supporting the use of L19IL2 for patients with aggressive B cell lymphoma.