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Blockade of TGF Beta Drive Hyper Progression on Small Cell Lung Cancer

To uncover mechanisms underlying divergent outcomes in patients with small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, we performed bulk transcriptomics of pre-treatment tumor biopsies from patients enrolled in a clinical trial of bintrafusp alfa, a bifunctional fusion protein targeting PD-L1 and TGF-β. We identified marked elevation of IFN-γ signaling and MHC class II expression. In contrast, Hyperprogressive disease (HPD) was associated with systemic immune suppression, impaired cytotoxicity, and, unexpectedly, tumor-intrinsic activation of TGF-β signaling and stemness. Functional studies confirmed that intact TGFβR2-mediated signaling is required for the hyperproliferative response to TGF-β blockade, revealing a context-dependent tumor-suppressive role for TGF-β.

Although TGF-β is widely regarded as an immunosuppressive driver in advanced cancers, our findings reveal a tumor-intrinsic, growth-constraining role for TGF-β signaling in SCLC. Disrupting this restraint can accelerate tumor progression, providing a mechanistic basis for HPD and highlighting the need for biomarker-driven strategies that account for tumor-intrinsic signaling when applying stromal-targeted immunotherapies.