Engineering ER-stress-driven immunogenic cell death with nanomedicine: UPR-axis control, DAMP signaling, and clinical translation

초록

Immunogenic cell death (ICD) converts stressed or dying tumor cells into an in situ vaccine by combining damage-associated molecular patterns (DAMPs) that activate innate sensing and adaptive immune priming. Yet ICD often is compromised by tumor adaptation to stress and microenvironmental editing mechanisms that degrade, sequester, or biochemically inactivate DAMPs and limit productive antigen presentation. This review discusses how nanomedicine can shift ICD from a chance byproduct of cytotoxic therapy to a deliberately programmed therapeutic endpoint. It does so by inducing endoplasmic reticulum (ER) stress along defined unfolded protein response (UPR) axes. It also controls the spatiotemporal emission of hallmark ICD signals, including calreticulin exposure, ATP release, and HMGB1 emission. Beyond increasing DAMP abundance, we introduce developing strategies to preserve DAMP bioactivity in the tumor microenvironment. These strategies regulate extracellular fate (e.g., ectonucleotidase-driven conversion of ATP to adenosine and state-dependent HMGB1 signaling). They also synchronize danger cues with tumor antigen exposure and cross-presentation. In addition, we present the concept of immunogenic ER stress without overt cell death as a tunable design window to facilitate vaccination-like priming. Finally, we summarize multifunctional nanoplatforms that integrate ICD programming with immune adjuvants and checkpoint blockade to turn cold tumors into hot tumors. We also discuss translational benchmarks, such as UPR/DAMP biomarker panels and type I interferon signatures. In addition, we highlight next-generation immune readouts, including spatial profiling and immunopeptidomics, to standardize comparisons and guide clinical translation.

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