Tumor-targeted IL2 promotes specific CD8(+) T cells private clonal expansion enhancing lymphoma control.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-026-03678-7.