Blockade of Tumor-Intrinsic TGFβ Signaling Drives Hyperprogression in Small Cell Lung Cancer

Abstract Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but the tumor-intrinsic consequences of blocking these pathways remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGFβ inhibitor, in small cell lung cancer (SCLC). Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met the criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n = 450), in higher frequencies with bintrafusp alfa than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGFβ signaling. Functional studies demonstrated that tumor-intrinsic TGFβ signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGFβ–high transcriptional state associated with inferior survival. These findings identify a context-dependent, growth-constraining function of TGFβ and support tumor-intrinsic biomarker guidance while targeting stromal immunosuppressive pathways. Significance: This study identifies tumor-intrinsic TGFβ signaling as a context-dependent growth restraint in SCLC and a driver of HPD following TGFβ blockade. A reproducible TGFβ–high mesenchymal state is linked to inferior survival, supporting biomarker-guided use of TGFβ–targeted immunotherapy.