Table 1.

Key characteristics of the actionable immune biomarkers, including detection methods, predictive implications, and disease specific relevance.

Biomarker	Measurement	Clinical implication & stratification	Evidence & future directions in thyroid cancer
PD-L1 expression	IHC: TPS or CPS	Gold standard for identifying “hot” tumors; CPS ≥ 50% serves as a threshold for ICI monotherapy in ATC/PDTC.	Spartalizumab responders cluster in high CPS groups; PD-L1–negative tumors did not respond (95).
TMB	WES or targeted panels (mut/Mb)	Predicts neoantigen load; TMB-high (≥10 mut/Mb) warrants consideration of ICI regardless of PD-L1 status.	Median TMB in ATC ≈ 5-7; responders tend to cluster in upper quartile (96).
IFN-γ gene signature	RNA-seq or PCR analysis of 6-gene or 18-gene IFN-γ response panel	Reflects T-cell inflamed TME; essential for differentiating “warm” from “immunosuppressed” niches.	TCGA analysis identifies an immunologically active cluster (C2) highly enriched for IFN-γ responsive genes with elevated predicted ICI efficacy (97).
M2 TAM score	CD163/CD68 ratio (IHC or RNA)	Key resistance marker; high scores justify combining ICIs with CSF-1R or VEGF inhibitors.	Enriched in aggressive ATC and RAIR-DTC niches; dense macrophage infiltration correlates with profound T-cell exhaustion and poor OS (98).
TLS	IF/IHC detection of CXCL13, LAMP3, PNAd, or gene markers	Superior predictor of OS; mature TLS presence indicates a permissive TME for B cell and T cell synergy.	High TLS density significantly correlates with improved DFS and active regional humoral immunity in PTC cohorts (34).

ATC, anaplastic thyroid carcinoma; CPS, Combined Positive Score; DFS, disease-free survival; DTC, differentiated thyroid cancer; ICI, immune checkpoint inhibitor; IF, immunofluorescence; IHC, immunohistochemistry; Mb, megabase; mut, mutations; OS, overall survival; PDTC, poorly differentiated thyroid cancer; PTC, papillary thyroid carcinoma; RAIR, radioiodine-refractory; TAM, tumor-associated macrophage; TCGA, The Cancer Genome Atlas; TLS, tertiary lymphoid structures; TME, tumor immune microenvironment; TMB, tumor mutation burden; TPS, Tumor Proportion Score; WES, whole-exome sequencing.