Researchers from Moffitt Cancer Center have found a new way to boost cancer immunotherapy by targeting a protein called macrophage receptor with collagenous structure, or MARCO. Their study, published in the Journal for ImmunoTherapy of Cancer, shows that blocking MARCO in combination with a type of immunotherapy known as anti-CTLA4 therapy, significantly enhances tumour regression in melanoma, the deadliest form of skin cancer.

The researchers found that inhibiting MARCO changes the behavior of certain immune cells in the tumour, leading to more immune cells entering the tumour and making the anti-CTLA4 therapy more effective. This new approach could help overcome resistance to current treatments, especially in tumours that usually have few immune cells, known as "cold" tumours.

"Our findings provide strong evidence that targeting MARCO can enhance the effectiveness of existing immunotherapies without requiring macrophage depletion," said James Mulé, iPh.D., associate center director for Translational Science at Moffitt and lead author of the study. "This discovery paves the way for new combination treatment strategies that could improve outcomes for patients with melanoma and potentially other cancers."

The study highlights that the combination of an anti-MARCO monoclonal antibody with anti-CTLA4 therapy significantly increases immune cell infiltration, including conventional dendritic cells, a key factor in activating a robust anti-tumour immune response. This effect was not observed when MARCO was targeted alongside anti-PD1 therapy, emphasising the importance of this approach in boosting anti-CTLA4 treatment.

These findings open new avenues for clinical research, with potential applications in treating patients who do not respond to current immunotherapy options. The study also suggests that incorporating MARCO-targeting strategies into neoadjuvant or adjuvant settings may help reduce cancer recurrence risks by enhancing immune priming within the tumor microenvironment.

More information: Hidenori Takahashi et al, Targeting MARCO in combination with anti-CTLA-4 leads to enhanced melanoma regression and immune cell infiltration via macrophage reprogramming, Journal for ImmunoTherapy of Cancer (2025). DOI: 10.1136/jitc-2024-011030