Abstract
Background:
Immune checkpoint inhibitors (ICIs) have shown limited efficacy in colorectal cancer (CRC), largely due to immunosuppressive tumor microenvironment (TME) including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Additionally, the off-target effects of ICIs can reduce drug accumulation in tumor tissues and lead to immune-related adverse events, further compromising their clinical utility.
Methods:
Using knob-into-hole technology, we developed ATAPL1, a bispecific antibody targeting both programmed death-ligand 1 (PD-L1) and tumor necrosis factor receptor 2 (TNFR2). In multiple subcutaneous and orthotopic CRC mouse models, ATAPL1 was evaluated for its tumor targeting, antitumor efficacy, immunomodulatory effects within the TME, and potential combinations with standard chemotherapies.
Results:
Compared with αPD-L1 or αTNFR2 monotherapy, ATAPL1 showed enhanced tumor accumulation and significantly improved antitumor efficacy, with no significant toxicity. It effectively modulated the TME by decreasing immunosuppressive Tregs and monocytic MDSCs (M-MDSCs), while promoting CD8+ T-cell activation and macrophage function. ATAPL1 also primed long-term immune surveillance, suggesting durable antitumor activity. Furthermore, ATAPL1 overcame chemotherapy resistance and exhibited superior therapeutic effects when combined with FOLFOX or FOLFIRI, compared with either treatment alone.
Conclusion:
These findings support ATAPL1 as a promising dual-targeted therapeutic strategy for CRC. It offers the potential to overcome immune and chemotherapy resistance, reduce off-target effects, and improve treatment outcomes through enhanced immune activation and tumor targeting.