T Cell Exhaustion and Dendritic Cell‐Mediated Tertiary Lymphoid Structures (TLSs) Modulation Affect Response to Neoadjuvant Chemoradiotherapy in Microsatellite Stable Rectal Cancer

Abstract Locally advanced rectal cancer (LARC) presents significant treatment challenges, particularly in microsatellite stable (MSS) patients, who often show limited response to immunotherapy. In these cases, neoadjuvant chemoradiotherapy (neoCRT) followed by surgery remains the recommended approach. However, the response to neoCRT varies significantly among LARC patients. In this study, the role of the tumor microenvironment (TME) is explored, focusing on early‐stage exhausted T cells (early‐Tex) and tertiary lymphoid structures (TLS), in predicting neoCRT response in MSS LARC. Through multi‐omics analyses, it is found that immune features of the TME, rather than mutational status, are more closely associated with treatment response. Within the TME, it is observed that early‐Tex cells, a subset with both similarities and distinct differences compared to previously described precursor exhausted T (Tpex) cells, are enriched in responders and correlated with favorable treatment outcomes. Additionally, it is identified that TLSs are more abundant, activated, and mature in responders compared to non‐responders. LAMP3⁺ dendritic cells (DCs) play a pivotal role in suppressing TLS formation, with IRF8 as a key transcriptional regulator, which may ultimately affect therapeutic response. These findings suggest early‐Tex cells and modulation of TLS by LAMP3⁺ DCs can serve as indicators for optimizing neoCRT in MSS LARC.