Although papillary thyroid carcinoma (PTC) is widely considered an immunologically cold tumor, detectable T-cell infiltration can influence disease progression in selected patients. Previous bulk analyses have linked cAMP-responsive element modulator (CREM) expression to a favorable progression-free interval and an inverse correlation with regulatory T-cell infiltration but have not resolved the cellular origin or functional state. In this study, we integrate single-cell RNA-sequencing data from a 23-sample PTC atlas with bulk Cancer Genome Atlas Thyroid Carcinoma (TCGA–THCA) validation. We show that CREM marks a T-cell receptor (TCR)-driven immediate early gene activation state in tumor-infiltrating T cells rather than a cAMP program; this state is consistently and modestly enriched within the FOXP3⁺ regulatory T-cell compartment, challenging the interpretation that bulk inverse Treg–CREM correlations reflect Treg-intrinsic repression. CREM-high T cells upregulate ANXA1, and permutation-controlled analysis identifies a candidate paracrine axis from CD4/CD8 T cells to the epithelial epidermal growth factor receptor (EGFR). At the bulk level, CREM expression correlates with reduced proliferation programs and is associated with a prolonged progression-free interval (multivariate HR 0.56, 95% CI 0.31–1.00, p = 0.050), with the effect direction preserved after immune and sex adjustment. Genome-wide differential expression and gene-set enrichment in an independent cohort (GSE193581) confirm that CREM-detected T cells are enriched for a TCR-driven immediate early transcriptional program, supporting the reinterpretation of CREM as a marker of TCR-driven IEG activation.

Skeletal muscle mass and radiation attenuation (RA) have been shown to be associated with chemotoxicity and survival in cancer patients. However, little is known about the clinical significance of adipose tissue RA, which has been hypothesized to be associated with tissue inflammation and insulin resistance. We investigated the association between adipose tissue RA, chemotoxicity, and survival in patients with metastatic colorectal cancer (mCRC) by performing a secondary analysis using data from a randomized controlled trial. We included 104 mCRC patients treated with standard first-line chemotherapy. Using diagnostic abdominal computed tomography (CT) scans, we assessed height adjusted (cm²) area and RA of skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) at the third lumbar vertebra, and calculated SM index (SMI), VATI, and SATI as cm²/m² based on stature. Associations between these body composition parameters and overall survival as well as chemotoxicity (NCI-CTCAE v 4.03) were evaluated using univariable and multivariable logistic and Cox regression analysis. Multivariable models evaluated body composition parameters, adjusted for age, sex, and significant clinically relevant covariates. Among the 104 patients in the cohort, 38 were female (36.5%). Mean age was 65.5 ± 9.5 years. 43 patients (41.3%) developed grade 3/4 toxicity. Pre-treatment SAT-RA was independently associated with grade 3/4 toxicities (OR = 0.78, 95% CI 0.62-0.98). Chemotherapy regimens and nutritional support were not associated with chemotoxicity. In the multivariable Cox analysis, SAT-RA (HR = 1.24, 95% CI 1.08-1.43) and SM-RA (HR = 0.74, 95% CI 0.61-0.90) were associated with shorter overall survival. Higher SAT-RA and lower SM-RA at baseline were associated with shorter overall survival of patients with mCRC, and lower SAT-RA was associated with increased chemotoxicity. These body composition alterations should be investigated in future chemotherapy related studies.