Cross-tissue atlas of mucosa-associated lymphoid tissue lymphomas reveals intratumoral heterogeneity and microenvironmental subtypes.

Mucosa-associated lymphoid tissue (MALT) lymphoma, a common primary extranodal B cell lymphoma that arises in diverse mucosal tissues, has a pathogenesis closely linked to the supportive lymphoma microenvironment (LME). However, its microenvironmental heterogeneity and therapeutic implications remain unclear. Here, we report a cohort of 89 MALT lymphoma samples from multiple anatomical sites, profiled by bulk (n = 89), single-nucleus (n = 16), and spatial (n = 9) RNA sequencing. Integrative analysis of 120 bulk transcriptomes from our cohort and two independent cohorts, guided by cell-type-resolved signatures derived from single-nucleus data, identifies three LME subtypes: mesenchymal, inflammatory, and depleted. Single-cell and spatial mapping further reveal distinct cellular compositions and interaction networks across these subtypes, particularly in relation to B cell activation and angiogenesis, suggesting distinct biological states and subtype-specific therapeutic vulnerabilities. This study establishes an LME-based classification framework for MALT lymphoma with biological and clinical relevance.