POSTN+ CAFs facilitate gastric cancer peritoneal metastasis by promoting ICAM-1-dependent tumor cell adhesion and CD8+ T-cell exhaustion.

BACKGROUND

Periostin (POSTN), an extracellular matrix protein secreted by cancer-associated fibroblasts (CAFs), critically shapes the tumor microenvironment. While POSTN contributes to tumor progression and immune regulation by modifying the microenvironment, its direct influence on T-cell activity and antitumor immunity remains unclear.

METHODS

In this study, single-cell and bulk RNA sequencing datasets were mined and combined with multiplex fluorescence immunohistochemistry to elucidate the role of POSTN+ CAFs. Primary CAFs were isolated and fibroblast lines with elevated POSTN expression were established to assess their direct impact on T-cells through functional assays. Transcriptome sequencing identified downstream regulatory pathways in POSTN+ CAFs. A mouse peritoneal metastasis model was used to evaluate the therapeutic potential of targeting POSTN+ CAFs in combination with immunotherapy.

RESULTS

Integration of single-cell transcriptomic datasets enabled the construction of a predictive model for gastric cancer peritoneal metastasis (GCPM) based on T-cell exhaustion-associated genes. POSTN was found to be primarily expressed by CAFs in GCPM tissues, with elevated levels correlating with poor clinical outcomes. Functionally, POSTN+ CAFs promoted adhesion and spheroid formation by autocrine activation of the AKT-NF-κB-ICAM-1 signaling pathway, facilitating peritoneal dissemination. Co-culture and in vivo experiments suggested that POSTN+ CAFs may promote CD8+ T-cell exhaustion via ICAM-1-ETV3 signaling, resulting in diminished effector function and cytokine production. Inhibiting POSTN downstream signaling with the integrin receptor antagonist Cilengitide, especially together with immune checkpoint blockade (anti-PD-1 and anti-CTLA-4), markedly reduced T-cell exhaustion and suppressed GCPM.

CONCLUSION

Our results indicate that POSTN+ CAFs are pivotal in maintaining an immunosuppressive microenvironment in GCPM. POSTN may facilitates CAFs-tumor and CAFs-T-cell interactions through ICAM-1, thereby promoting metastasis and promoting immune evasion. Targeting the POSTN-ICAM-1 axis may provide a therapeutic approach to enhance immunotherapy efficacy and enhance immunotherapy outcomes in patients with GCPM.