STAT3/NF-κB signaling axis in macrophage and myeloid-derived suppressor cell driven immune evasion in lung cancer

Abstract

Immune checkpoint blockade (ICB) has brought transformative advances to lung cancer management; nevertheless, immunosuppressive tumor microenvironment (TME)-mediated therapeutic resistance constitutes a prominent unsolved bottleneck, mainly originating from the sustained buildup of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Among its key regulators, TAMs and MDSCs play pivotal roles in dampening antitumor immunity through activation of the STAT3/NF-κB signaling axis that structurally locks myeloid cells into an immunosuppressive and therapy-resistant state. This axis integrates cytokine, metabolic, and stress cues to promote chronic inflammation, immunosuppressive gene expression, and immune checkpoint upregulation. Crosstalk between STAT3 and NF-κB amplifies IL-6, IL-10, and TNF-α loops, sustaining TAM and MDSC recruitment, polarization, and suppressive activity. Furthermore, this pathway drives angiogenesis and immune exclusion, contributing to poor immunotherapy responses. By shifting the focus from isolated molecular targets to this integrated inflammatory-metabolic network, we outline emerging therapeutic strategies, such as small-molecule inhibitors and combination regimens with immune checkpoint inhibitors, that hold the potential to dismantle this central inflammatory hub of lung cancer and restore durable antitumor immunity. A deeper understanding of STAT3/NF-κB-driven myeloid reprogramming may open new avenues for restoring effective antitumor immunity in lung cancer in this mechanistic review.