PD-1 Blockade Enhances Therapeutic Effects of Anti-CEA 177Lu-DOTA-M5A in Colorectal Cancer CEA-Transgenic Mice

Tumor-targeted radioimmunotherapy (RIT) has the dual capability of delivering ionizing radiation to cancer cells while modulating the tumor microenvironment (TME) to enhance immune responses. These immune-stimulatory properties suggest that RIT could synergize with PD-1 blockade. However, the precise immune mechanisms underlying this potential synergy remain unclear. Here we show that ¹⁷⁷Lu-DOTA-M5A, the radiolabeled antibody against carcinoembryonic antigen (CEA), induces tumor regression and alters the TME when combined with PD-1 blockade in a colorectal cancer (CRC) model. Using in vitro uptake assays and in vivo studies in CEA-transgenic mice, we found that low-dose ¹⁷⁷Lu-DOTA-M5A (2.5 MBq) combined with anti-PD-1 achieved complete tumor control, with −6% growth rate, in contrast to limited efficacy from either monotherapy. This combination extended survival by more than 300% compared to controls, with no median survival reached. Remarkably, this effect was equivalent to that of high-dose monotherapy (5 MBq), indicating a potent synergistic interaction. Immune profiling revealed that RIT altered lymphocyte infiltration, while the combination therapy shifted tumor-associated macrophages toward a pro-inflammatory phenotype. These immune-modulating effects occurred without inducing myelotoxicity. Our findings suggest that PD-1 blockade potentiates the therapeutic efficacy of ¹⁷⁷Lu-DOTA-M5A, supporting its development as a safe and effective combination strategy for CRC therapy.