A bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β1 (SHR1701) enhanced preclinical antitumor activity in oral squamous cell carcinoma.

BACKGROUND

Oral squamous cell carcinoma (OSCC) is characterized by a profoundly immunosuppressive tumor microenvironment (TME), which limits the clinical efficacy of immune checkpoint inhibitors (ICIs) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis. Transforming growth factor-beta (TGF-β) is a key immunosuppressive mediator in OSCC and is associated with disease progression and resistance to immunotherapy. SHR-1701 is a bifunctional fusion protein designed to simultaneously block PD-L1 and sequester TGF-β. This study investigated the biological relevance of TGF-β1 in OSCC and evaluated the preclinical antitumor activity and immunomodulatory effects of SHR-1701.

METHODS

The expression and prognostic significance of TGF-β isoforms were analyzed by using The Cancer Genome Atlas (TCGA) datasets and a retrospective cohort of OSCC patients. The functional effects of SHR-1701 on OSCC cell lines were evaluated in vitro. T-cell-dependent cytotoxicity was evaluated by using an in vitro co-culture system. The antitumor efficacy, immune modulation, and safety of SHR-1701 (alone or in combination with cisplatin and paclitaxel) were further examined in a patient-derived xenograft (PDX) model involving autologous T-cell adoptive transfer.

RESULTS

Clinical and transcriptomic analyses demonstrated a significant association between TGF-β1 expression and aggressive disease features in OSCC. SHR-1701 exerted notable functional effects on OSCC cells in vitro and enhanced T-cell-mediated antitumor responses in vivo. In PDX models, compared with monotherapies, SHR-1701 exhibited superior antitumor activity, and combination treatment with chemotherapy further increased therapeutic efficacy and immune engagement.

CONCLUSION

These findings demonstrate that TGF-β1-associated immunosuppression plays a critical role in OSCC progression and therapeutic resistance. The dual targeting of PD-L1 and TGF-β signaling with SHR-1701 effectively remodels the immunosuppressive TME and enhances antitumor immune responses in preclinical models, thus providing a strong translational rationale for further clinical evaluation of SHR-1701 in OSCC.