Tumor immunotherapies enhance CD8+ T cell function, yet heterogeneous responses in "cold" and "hot" tumors remain a challenge. Although biomechanical cues modulate T cell cytotoxicity, strategies to harness these forces for broad antitumor potentiation remain elusive. Here, integrating pan-cancer single-cell RNA sequencing data, we identify cofilin 1 (CFL1) as a determinant of immunotherapy response. CFL1 overexpression synergizes with CD8+ T cell-targeted immunotherapy across tumor types, driving intratumoral T cell expansion while rendering tumors physically vulnerable. Mechanistically, CFL1 hyperactivation induces F-actin bundling and actin rod accumulation, elevating cytoskeletal tension to facilitate immun... More
Tumor immunotherapies enhance CD8+ T cell function, yet heterogeneous responses in "cold" and "hot" tumors remain a challenge. Although biomechanical cues modulate T cell cytotoxicity, strategies to harness these forces for broad antitumor potentiation remain elusive. Here, integrating pan-cancer single-cell RNA sequencing data, we identify cofilin 1 (CFL1) as a determinant of immunotherapy response. CFL1 overexpression synergizes with CD8+ T cell-targeted immunotherapy across tumor types, driving intratumoral T cell expansion while rendering tumors physically vulnerable. Mechanistically, CFL1 hyperactivation induces F-actin bundling and actin rod accumulation, elevating cytoskeletal tension to facilitate immunological synapse formation. Conversely, CFL1 inactivation through phosphorylation or our newly identified lactylation correlates with poor outcomes. Combination therapy using adeno-associated virus delivering constitutively active CFL1 and PD-1 blockade achieves near-complete tumor eradication. Together, our findings position CFL1 as a biomechanical checkpoint governing tumor vulnerability to CD8+ T cells through immunological synapse licensing, offering a strategy to overcome immunotherapy resistance.
