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 de novo immunity, but by amplifying pre-existing immune programs. In this model, checkpoint release may lead to either productive tumor control or maladaptive activation and accelerated progression, depending on the baseline immune architecture of the host tissue. Understanding HPD through the lens of organ-context immune wiring has major translational implications for predictive biomarkers, stratification strategies, and the design of context-aware immunotherapy.