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

ABSTRACT 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 177 Lu‐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 177 Lu‐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 177 Lu‐DOTA‐M5A, supporting its development as a safe and effective combination strategy for CRC therapy.