Tumor heterogeneity shapes responses to STING and LTβR-mediated TLS induction

Tertiary lymphoid structures (TLSs) are associated with improved anti-tumor immunity and favorable clinical outcomes across multiple cancer types. Therapeutic induction of TLSs is a promising strategy to stimulate potent anti-tumor immunity in cancer patients. However, the impact of tumor heterogeneity on therapeutic TLS induction remains poorly understood. Using four pancreatic cancer models derived from KPC mice, we examined the effect of combined STING and LTβR stimulation on TLS induction. Although treatment elicited variable anti-tumor responses across tumor models, robust TLS formation was observed only in KxPxCx tumors. Comparative transcriptomic analyses demonstrated that TLS-permissive KxPxCx tumors exhibited distinct inflammatory and stromal remodeling programs, including enrichment of fibroblastic, extracellular matrix remodeling, wound-healing, and TGFβ-associated pathways. Despite these differences in transcriptional profiles, the expression of STING- and LTβR-associated proteins and direct tumor cell responsiveness to stimulation did not explain the selective capacity for TLS formation. These findings demonstrate that pancreatic tumor heterogeneity profoundly influences responsiveness to therapeutic TLS induction and identify distinct transcriptional characteristics associated with a TLS-permissive tumor microenvironment.