Innate immune signaling-driven myeloid remodeling in cancer: inflammatory amplification, immune suppression, and...

Innate immune signaling is a central regulator of cancer immunity, but its effects are highly context-dependent. Acute and spatially controlled innate immune activation can promote dendritic-cell maturation, antigen presentation, and cytotoxic lymphocyte recruitment. In contrast, chronic, systemic, or therapy-induced inflammatory signaling often redirects the tumor ecosystem toward suppressive myeloid remodeling. This review discusses how innate immune pathways reshape myelopoiesis, macrophage polarization, MDSC activation, tumor-associated neutrophil recruitment, and stromal-myeloid inflammatory niches. We focus on selected signaling axes that represent distinct layers of innate inflammatory regulation, including cytokine-mediated myeloid instruction, inflammasome activation, nucleic-acid sensing, chemokine-driven recruitment, stromal transcriptional integration, and lipid-mediator signaling. These axes include IL-4/IL-4Rα, IL-1α/IL-1β, TGF-β, interferon signaling, NLRP3 inflammasome activation, STING, STAT3, IL-8/CXCR2, CCR2, and CysLTR1. These pathways can expand suppressive myeloid output from the bone marrow, reinforce tumor-associated macrophage states such as TREM2⁺, SPP1⁺, and NLRP3⁺ macrophages, and promote MDSC- and neutrophil-mediated resistance to immune checkpoint blockade. We also summarize tissue, spatial, and peripheral biomarkers that may identify myeloid-dominant immune resistance. Finally, we discuss therapeutic strategies aimed at blocking inflammatory drivers, inhibiting inflammasome-dependent amplification, preventing suppressive myeloid recruitment, and reprogramming established myeloid niches. Rather than cataloguing individual myeloid subsets or isolated inflammatory pathways, this review integrates systemic myelopoiesis, local TAM/MDSC/TAN remodeling, stromal-myeloid spatial niches, and therapy-induced inflammatory feedback into a unified framework for understanding and targeting immune checkpoint blockade resistance.