The Big Questions in Cancer Immunotherapy: Why Do “Cold” Tumors Stay Invisible to the Immune System?

Immune checkpoint inhibitors have demonstrated that the immune system can control—and occasionally eradicate, advanced cancer. Yet this success depends on something that is easy to overlook: there must first be an antitumor immune response available for checkpoint blockade to amplify.

In many solid tumors, that response is weak, spatially restricted, or almost absent.

These tumors are commonly described as immunologically “cold. ” They are characterized by limited productive T-cell infiltration and a tumor microenvironment that does not support sustained antitumor immunity. Pancreatic cancer, microsatellite-stable colorectal cancer, prostate cancer, and subsets of ovarian, breast, and other malignancies frequently display features of this phenotype.

But “cold” is a pathological description, not a mechanism.

Some tumors avoid generating an immune response. Others generate tumor-reactive lymphocytes but prevent them from entering malignant tissue. Still others permit immune infiltration but establish local conditions that make effective tumor-cell killing extraordinarily difficult.