What if a melanoma drug works not by attacking the cancer directly, but by removing the cells that stop the immune system from attacking it? This study points to that unexpected possibility. Melanoma remains a significant and rising health burden in the United States.

Immune checkpoint inhibitors have improved outcomes, but a significant proportion of tumors are or will become resistant to these therapies. Myeloid-derived suppressor cells pose a significant obstacle to successful antitumor immunity and effective immune checkpoint treatment.

The study explores whether MCL1 inhibitors can target these cells and improve treatment. The researchers compared the treatment in mice with working immune systems and mice lacking functional lymphocytes. Tumor growth fell in the mice with working immune systems, but not in the mice without those immune cells.

That result points to an unusual role: the treatment does not mainly work by directly killing the tumor, because inhibiting MCL1 in tumor cells had little to no direct effect on cell viability. Changing MCL1 in the tumor cells was not enough to slow tumor growth, because MCL1 knockdown did not inhibit tumors in immunocompetent mice.

Think of the tumor as a building protected by a hostile security team. The treatment appears to work by changing the surrounding security system—the immune cells—rather than simply breaking the building itself. The researchers examined immune cells inside tumors from patients whose melanoma had returned after anti-PD-one checkpoint treatment, using single-cell RNA sequencing.

The analysis identified cluster four as MDSC-like, with low antigen-processing machinery and high expression of immunosuppressive genes within the myeloid cells. Further gene-expression analysis showed that these MDSC-like cells expressed high levels of MCL one compared with other cells in the tumors.

Prior reports identified MCL one as a critical factor in MDSC survival and development, making this pathway a possible target for therapeutic study. In treated tumors, the immune-suppressing cells were significantly reduced.

At the same time, the findings involved both CD8 T cells and highly activated CD8 T cells, linking the treatment with stronger antitumor immune activity. The treatment effectively killed human immune-suppressing cells, while no changes were observed in the multiplication of either major type of human T cell at the tested concentrations.

It also did not alter the ability of human CD8 T cells to produce important immune signals at a concentration that killed most of the immune-suppressing cells, or at lower concentrations. The findings indicate that the treatment does not negatively impact T cell function, allowing these cells to maintain their normal functionality in the absence of the immune-suppressing cells.

The treatment strongly reduces the suppressive immune cells that can shield melanoma, while leaving the growth and cancer-fighting signals of activated T cells largely intact. That selectivity is why it could pair well with immune therapy. The treatment was then combined with checkpoint treatment in mice.

Together, the two treatments significantly inhibited tumor growth compared with no treatment or either treatment alone. The combination was tolerable at the tested doses and did not significantly reduce mouse weight. The treatment therefore enhanced the efficacy of checkpoint treatment in this model.

The study is a proof of concept for bringing future versions of these drugs into melanoma clinical trials. It provides evidence that blocking MCL1 could enhance immunotherapies against melanoma. The current generation of MCL1 inhibitors is not suitable for clinical use, but future generations may become a tool for targeting solid tumors and improving patient responses to checkpoint treatment.

The study suggests that blocking MCL1 can reduce immune-suppressing cells while leaving important attacking immune cells functional, and that pairing this approach with checkpoint treatment can slow melanoma growth more effectively than either alone.