Can tissue immune states shape the risk of hyperprogressive disease?

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by unlocking antitumor T-cell responses across multiple cancer types. However, a subset of patients experience rapid acceleration of disease progression shortly after ICI initiation, a phenomenon termed hyperprogressive disease (HPD). Although HPD remains clinically heterogeneous, emerging evidence suggests that HPD is not solely a stochastic anomaly, but may result from an immune rewiring failure triggered by checkpoint release in chronically inflamed, myeloid-dominated, or tolerogenic host organs that are permissive for tumor growth. Mechanistic studies in metabolic dysfunction-associated steatohepatitis (MASH)-associated hepatocellular carcinoma show that PD-1 blockade can fail to restore effective antitumor immunity and instead exacerbate pathogenic T-cell-mediated injury. Related findings in colitis-associated colorectal cancer, chronic lung inflammation, and glioblastoma suggest how pre-existing immune circuits shaped by inflammation, fibrosis, metabolic dysfunction, or immune privilege can constrain productive immune rewiring. We synthesize these organ-specific archetypes into an organ-context model in which ICIs act not by generating