B7-H3 May Be Doing More Than Marking Prostate Cancer

B7-H3 has become one of the most interesting targets in advanced prostate cancer, especially for antibody-drug conjugates and other targeted treatments. A new Cancer Discovery study suggests that B7-H3 may not simply sit on the surface of tumour cells: it may actively help the cancer suppress the immune system and resist treatment.

The researchers found that B7-H3 affects myeloid-derived suppressor cells, immune cells that can protect tumours from attack. Through MAPK signalling, B7-H3 pushes some of these cells into a state that leads them to attract even more suppressive immune cells. When B7-H3 was blocked or removed, these protective cells decreased and tumour growth slowed in preclinical models.

But the tumour found another way to adapt. Blocking B7-H3 caused suppressive immune cells to release SPINK1, which then activated cancer-associated fibroblasts through the EGFR–MEK–ERK pathway. These fibroblasts changed the tissue around the tumour and partly protected it from B7-H3-targeted treatment.

The most interesting result came from combining a B7-H3 antibody with trametinib, a MEK inhibitor already used in cancer treatment. By blocking both B7-H3 and this escape pathway, the combination produced more durable tumour control in preclinical models of castration-resistant prostate cancer.

This could be important because B7-H3 is already being tested as a target in prostate cancer. The study suggests that simply attacking B7-H3-positive cells may not be enough: it may also be useful to block the backup pathways the tumour activates when B7-H3 is inhibited.

For now, the work is still preclinical, but it adds an important new idea to the B7-H3 story. The target may be valuable not only because it is common on prostate cancer cells, but also because it seems to help create the immune-suppressive environment that protects them.

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