Illa Bochaca, I. | Search bioRxiv

bioRxiv2026

Cross-species spatial profiling links progranulin to an immune suppressive niche in brain metastasis

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of brain metastasis (BM), demonstrating intracranial response rates and durability not previously seen with other therapies. However, approximately 50% of patients do not respond to ICI, and the brain-specific interactions that shape anti-tumor immunity remain poorly understood. We profiled five syngeneic BM models using spatial transcriptomics, identifying myeloid-rich niches enriched for interferon-responsive and disease-associated microglia (DAM)-like programs. Ligand-receptor colocalization analyses identified progranulin (PGRN) as a candidate mediator of these niches. Host- or tumor-cell Grn loss reduced BM burden, and Grn-deficient macrophages exhibited altered metabolic programs and tumor-cell engulfment in vitro. Across independent human BM datasets, GRN expression was associated with conserved lysosomal and DAM-like myeloid programs, and GRN-high myeloid regions colocalized with immunosuppressive signatures and dysfunctional CD8+ T cell states. These cross-species findings identify PGRN as a candidate mediator of the BM immune niche and support further investigation of its therapeutic relevance.

cancer biology↗

bioRxiv2026

Melanoma evolution in the lymph node shapes systemic outcomes

Lymph node (LN) metastasis predicts poor patient outcomes, but the mechanistic drivers that shape metastatic fitness, immune evasion, and clinical impact remain elusive. While preclinical models indicate that active tumor adaptation is necessary for LN metastasis, observations of clonal heterogeneity in human tumors has supported a stochastic model of passive and continuous seeding. Reconciling LN metastasis as a passive or active process is essential to understanding if LN metastasis is simply a marker of disease progression or a clinically informative therapeutic target. Here, we report evidence that LNs are active niches that facilitate ongoing melanoma evolution to progressively subvert immune surveillance and enable progression. To construct a spatial trajectory of LN metastasis, we examined paired primary melanomas and metastatic sentinel LNs through integrated genomic, phenotypic, and immunologic analyses. In contrast to a model of continuous seeding, we observe that early dissemination from the primary tumor is followed by extensive intra-nodal diversification, indicating that metastatic outgrowth requires ongoing adaptation within the LN. As clones evolve in the LN, they re-differentiate towards a melanocytic state and reprogram the microenvironment for immune exclusion. In further evolved clones, loss of inflammatory interferon signaling and induction of p53 and mitochondrial stress are associated with decreased overall survival. Collectively, these results implicate the LN as a critical battleground for melanoma progression, where tumor evolution drives adaptation and immune escape to biologically link regional metastasis to patient survival.

cancer biology↗