Targeting the non-canonical immune checkpoint MUC1-C enhances anti-PD-1 therapy in solid tumors

Immune checkpoint inhibitors (ICIs), particularly monoclonal antibodies targeting PD-1 and PD-L1, have revolutionized cancer therapy by enhancing antitumor immune responses. Despite their clinical success across multiple tumor types, several challenges remain, such as suboptimal response rates, which underscores the need for novel combinatorial strategies. MUC1-C, a transmembrane glycoprotein aberrantly expressed in many cancers, has recently emerged as a non-canonical immune checkpoint associated with T cell depletion and dysfunction within tumor microenvironment, thereby promoting immune evasion. Here, we present a novel immunotherapeutic strategy that concurrently targets canonical and non-canonical immune checkpoints by combining anti-PD-1 with PAb001, a humanized IgG1 antibody developed by Peptron that binds MUC1-C with high affinity ( K D < 1 nM). In a syngeneic tumor model utilizing MC38-hMUC1, a murine colon adenocarcinoma cell line engineered to express human MUC1, combinatorial treatment with 1H7 (a surrogate murine antibody targeting human MUC1-C) and an anti-mouse PD-1 antibody exhibited robust antitumor activity, resulting in marked tumor growth inhibition (TGI = 91.3%). Ongoing studies are evaluating the combinatory efficacy of additional anti-MUC1 antibodies and ICIs to further define the selective advantages of PAb001 in treating malignant tumors, and are also aimed at elucidating the molecular mechanisms underlying its therapeutic activity. In conclusion, these findings support the therapeutic potential of a dual-checkpoint blockade strategy that concurrently targets canonical and non-canonical pathways, which offers a promising approach to address limitations inherent to current ICI-based therapies.