Figure S5 Blocking WNT7A synergizes with ICB.

How cancer-associated fibroblasts (CAFs) dictate CD8+ T cell dysfunction during lung cancer remains unclear. Through single-cell analysis of 84 human NSCLC samples, we identified insulin-like growth factor 2 (IGF2) as a key immunosuppressive factor in a specific CAF subset. IGF2+ CAF infiltration correlated with CD8+ T cell dysfunction. Fibroblast-specific IGF2 knockout enhanced antigen presentation cell-autonomously via major histocompatibility complex class I (MHC-I), boosting CD8+ T cell effector function, tumor suppression, survival, and PD-1 blockade synergy. Mechanistically, IGF2 sustained MYC signaling to up-regulate DNA methyltransferase 1 (DNMT1), which methylated the STAT1 promoter, epigenetically silencing STAT1. This impaired MHC-I presentation and CD8+ T cell activation. Clinically, high IGF2 levels associated with reduced CD8+ T cell cytotoxicity and poor outcomes. An IGF2+ fibroblast signature predicted worse response to immunotherapy in multiple cohorts. Our findings establish IGF2 as a central regulator of CAF-mediated immunosuppression and a stromal target for enhancing immunotherapy in lung cancer.

Association of lnc-WAL expression with the clinical outcome of patients with multiple cancers.

Univariate and multivariate Cox proportional hazard analyses of DFS in 189 patients with TNBC.

Univariate and multivariate Cox proportional hazard analyses of OS in 189 patients with TNBC.

2D interaction maps of small molecules obtained via protein screening of the ChemBridge library.

Figure S2 Blocking WNT7A leads to an increase in MHC-I expression.

lnc-WAL inhibits β-catenin phosphorylation by physically obstructing AXIN.

lnc-WAL promotes MDA-MB-231 cell growth and metastasis in vivo.

Figure S4 Inhibition of WNT7A leads to the upregulation of MHC-I via the NF-κB pathway.

Figure S6 Discovery of small chemical inhibitors targeting WNT7A–FZD5.

Identification of Wnt/β-catenin pathway-associated lncRNAs.

lnc-WAL promotes malignant progression of TNBC cells.

Primer sequences for RACE analyses.

Figure S3 WNT7A blockage inhibits tumor growth and enhances anti-tumor immunity.

Figure S1 High WNT7A expression correlates with low CTL cell infiltration, reduced MHC-I expression, and unfavorable patient survival.

Reagent or resource for this project.

Lnc-WAL promotes malignant progression of TNBC cells.