Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures by Zhonghui Tang,1,2,18,* 5,6,12,18 Chunqing Wang,9,10 Zhuoxuan Wang,12 Changjun Yin,12,13 Jianping Guo,12 Shiping Liu,4,14,15,16,* Sui Peng,12,17,* and Ming Kuang5,12,19,* ISBN 101016/JCCELL202503011 instant download

Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid structures by Zhonghui Tang,1,2,18,* 5,6,12,18 Chunqing Wang,9,10 Zhuoxuan Wang,12 Changjun Yin,12,13 Jianping Guo,12 Shiping Liu,4,14,15,16,* Sui Peng,12,17,* and Ming Kuang5,12,19,* ISBN 101016/JCCELL202503011 instant download

SUMMARYTertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, oftenlinked to enhanced immunotherapy responses and better clinical outcomes. However, the factors drivingTLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possessa niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLSmaturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumorcontrol, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potentialstrategy to improve antitumor responses and immunotherapy outcomes.