An ATXN2-linked stress granule transcript program marks proliferative and CD8-low states in colorectal cancer.

Immune checkpoint blockade benefits only a minority of colorectal cancer patients, and many tumors show immune-cold phenotypes at the transcript level, especially in microsatellite-stable (MSS) disease. Stress granules are conserved ribonucleoprotein assemblies that form under metabolic and proteotoxic stress and include the RNA-binding protein ataxin-2 (ATXN2). However, it remains unclear whether stress-granule-related tumor programs consistently track immune-cold colorectal cancer (CRC) states across independent cohorts. Here, we tested whether a compact stress-granule-related transcript program anchored on ATXN2 (CS_ATXN2) is associated with reduced CD8 cytotoxic transcript signal in bulk CRC beyond proliferation, hypoxia, and tumor purity. We analyzed three independent bulk CRC cohorts (total n = 1220) using multivariable models adjusting for proliferation, hypoxia, and tumor purity, pooled by random-effects meta-analysis. Program-level robustness and relative specificity were assessed using a P_BODY control, leave-one-gene-out testing, and expression-matched random gene sets. Four orthogonal immune deconvolution frameworks were applied, and patient-level pseudobulk analysis was performed in a CRC single-cell atlas. CS_ATXN2 was consistently associated with lower CD8 cytotoxic transcript signal across all three cohorts (pooled standardized beta = -0.159, 95% CI -0.215 to -0.103, p < 0.001, I² = 21.2%), surviving stromal adjustment and not reproduced by a P_BODY control. Immune deconvolution analyses provided convergent but not uniform support for reduced inferred lymphocyte signals in CS_ATXN2-high tumors. Patient-level single-cell analysis identified CXCL8 and LIF as candidate extracellular transcripts elevated in CS_ATXN2-high malignant cells (FDR < 0.05). In summary, CS_ATXN2 is a reproducible transcriptomic marker of proliferative and CD8-low CRC states.