Regulatory mechanisms and functions of RORγt⁺ antigen-presenting cells in the tumor microenvironment of non-small cell lung cancer

Abstract

Non–small cell lung cancer (NSCLC) shows heterogeneity in benefit from immunotherapy across stages and biomarkers, underscoring the need to define tumor-microenvironment (TME) circuits that shape immune activation, spatial organization, and adaptive resistance. Beyond classical APCs, an emerging family of MHC-II⁺, RORγt-expressing APCs—including group 3 innate lymphoid cells (ILC3s), extrathymic AIRE⁺ cells (eTACs), and DC-like populations—has been reported in barrier and lymphoid tissues, shaping type-3 immunity, Th17 differentiation, tolerance, and tertiary lymphoid structure (TLS) biology. Direct phenotypic and functional characterization of bona fide RORγt⁺ APCs in human NSCLC remains limited, and many tumor-derived signals more plausibly reflect RORC-associated, type-3–skewing APC programs rather than confirmed RORγt⁺ identities. In this hypothesis-driven review, we integrate RORγt-linked APC biology, Th17 plasticity, and NSCLC immunobiology to propose a “TME signaling–RORγt-related APC programs–Th17 axis.” To prevent terminology drift, we adopt an evidence-tiered framework distinguishing bona fide RORγt⁺ APCs from inferred RORγt-associated states, and we describe functional variation using module-based descriptors (APC-program–high vs tolerogenic/TLS-linked bias). We further outline how cytokine–chemokine modules—notably CCR6–CCL20—and spatial TLS niches might couple APC programs to Th17 positioning and downstream CD8⁺ T-cell immunity, while emphasizing context-dependent bidirectionality (immune-supportive vs tumor-promoting inflammation). Finally, we highlight two regulatory modules—hypoxia–lactate/adenosine and lipid-ligand tuning of the RORγt ligand-binding domain—as plausible upstream levers that could remodel antigen presentation and type-3 outputs. Translational implications—including RORγt agonism, TME remodeling, and stage-aware biomarker hypotheses with minimally invasive profiling in malignant pleural effusion—are presented as testable hypotheses requiring validation in stage-resolved human NSCLC cohorts and mechanistic studies.