Regulated Tumor-cell Death in Chemoimmunotherapy: Mechanisms, Biomarkers, and Clinical Translation.

Abstract

Immune-checkpoint blockade is most effective when tumor antigens are visible, innate sensing is intact, and effector lymphocytes can enter the tumor microenvironment. This narrative review evaluates regulated tumor-cell death as the mechanistic interface between chemotherapy and checkpoint inhibition. PubMed/MEDLINE and ClinicalTrials.gov were searched for English language records published from January 2005 through August 2026. Consensus definitions, mechanistic studies with functional immune endpoints, randomized phase III trials and mature updates, and longitudinal human translational studies were prioritized. Immunogenic cell death is best considered a functional immunologic outcome of a dying-cell context rather than a death pathway equivalent to ferroptosis, necroptosis, or pyroptosis. Chemotherapy may promote antigen release, innate sensing, dendritic-cell activation, and T-cell priming, but it may also deplete immune effectors or provoke suppressive inflammation. Pivotal chemoimmunotherapy trials demonstrate clinical benefit in several cancers; however, efficacy does not establish that cell death was immunogenic or identify a specific death program. Ferroptosis, necroptosis, and pyroptosis remain predominantly preclinical in this setting. A dynamic biomarker framework should integrate proximal danger signals with antigen presentation, tumor-reactive T-cell expansion, and spatial immune remodeling. Regimen design should define the intended immune-conditioning window and verify adaptive priming with longitudinal tissue, blood, and imaging measurements. This approach may guide sequencing, de-escalation, and mechanism-based treatment changes when tumor shrinkage occurs without immune priming.