Integrating computational engines to identify TSPAN6 as a migrasome-associated target for immunotherapy sensitization
Year: 2026
Type: article
Abstract: Migrasomes, recently discovered extracellular organelles, are implicated in cancer progression and immune regulation. Nevertheless, their roles in cancer immunotherapy resistance remain poorly understood. To address this gap, we integrated cutting-edge computational engines to identify migrasome-associated targets modulating cancer immunotherapy. Using the Cancer Immunology Data Engine (CIDE) covering 5,957 patients across 17 tumor types, TSPAN6 was identified as significantly associated with adverse immunotherapy outcomes. Pan-cancer validation across the TCGA, ICGC, and CPTAC cohorts confirmed that elevated TSPAN6 expression significantly correlates with adverse prognosis. Using the pan-cancer atlas of over 4.4 million cells, we revealed the specific expression of TSPAN6 in malignant cells. Additionally, TSPAN6-high malignant cells significantly up-regulate immune checkpoint genes including CD274, NECTIN2, and LGALS9, thereby enhancing immunosuppressive interactions with exhausted T cells. Genetic ablation of TSPAN6 in co-culture models enhanced anti-tumor immunity, functionally validating this mechanism. Spatial transcriptomics further demonstrated TSPAN6 enrichment in tumor cores and its significant downregulation in immunotherapy responders compared to non-responders. In our validation cohorts, paired serum samples from 44 cancer patients showed significantly decreased TSPAN6 levels following immunotherapy. To overcome TSPAN6-mediated resistance, we computationally screened 1,615 FDA-approved compounds for inhibiting TSPAN6. Among these drugs, mitoxantrone demonstrated high-affinity binding to TSPAN6 through hydrogen bonding and hydrophobic interactions with TSPAN6. Collectively, our findings establish TSPAN6 as a migrasome-related regulator driving adverse immunotherapy outcomes and responses. Targeting TSPAN6, potentially with mitoxantrone, presents a potential strategy to enhance immunotherapy efficacy.
Source: Frontiers in Immunology
Authors: Liwen Fang, Hui Pan, Yihao Zhu
Institutions: Changhai Hospital, Second Military Medical University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7129216101