Remodeling the tumor immune microenvironment: mechanisms of crosstalk between regulated cell death macrophages

Abstract

Although advances have been made in tumor immunotherapy, the immunosuppressive tumor microenvironment and treatment resistance still limit durable clinical benefit. Rather than functioning exclusively as terminal cytotoxic phenomena, regulated cell death (RCD) pathways generate surface cues, soluble mediators and cellular cargo that reshape immune responses. Here, we review the reciprocal interactions linking tumor-associated macrophages (TAMs) with apoptosis, necroptosis, pyroptosis, autophagy-related regulation, ferroptosis and cuproptosis. We examine how death execution, the kinetics and magnitude of tumor cell death, membrane integrity, and signal accessibility shape RCD-derived signals, and how macrophage lineage, functional state and signal-processing capacity determine their inflammatory and antitumor consequences. These reciprocal interactions regulate corpse clearance, antigen presentation, metabolic adaptation, tumor progression, and therapeutic resistance, while macrophages can in turn alter the susceptibility of viable tumor cells to death. We further discuss crosstalk among RCD pathways, extracellular vesicle-mediated communication, microbiota-related regulation and spatiotemporal reconfiguration during tumor progression and treatment. Finally, we evaluate nanomedicine strategies that coordinate tumor-selective RCD with macrophage regulation while emphasizing limitations in cell-type specificity, safety, patient selection and clinical evidence. This framework may guide more precise intervention along the RCD–macrophage axis.