Core Viewpoint - The article discusses the significance of Total Neoadjuvant Therapy (TNT) in the treatment of locally advanced rectal cancer (LARC) and highlights the need for a deeper understanding of the immune remodeling mechanisms involved in its efficacy [3][6]. Group 1: Treatment Strategies and Mechanisms - LARC accounts for over one-third of both incidence and mortality in colorectal cancer, which is the third most common and the second deadliest cancer globally [3]. - Recommended treatment strategies for LARC include TNT or neoadjuvant chemotherapy (nCT), with additional options like radiotherapy for cases with poor response [3]. - The immune remodeling mechanisms behind the efficacy of TNT remain unclear, necessitating further research into the tumor microenvironment (TME) changes induced by this therapy [6]. Group 2: Research Findings - A study published in Cancer Cell reveals that TNT significantly remodels the immune microenvironment in LARC, with CD8+ T cells and endothelial cells interacting as a potential key factor for clinical efficacy [4][10]. - The research utilized single-cell RNA sequencing and spatial transcriptomics to analyze pre- and post-treatment samples, showing that TNT is associated with a reduction in regulatory T cells (Treg) and an increase in IFNG+ CD8+ effector memory T cells, which may enhance complete response rates [6][7]. - The abundance of tumor-infiltrating CD8+ T cells post-TNT correlates with the enrichment of ACKR1+ endothelial cell subpopulations, which are activated by IFNγ released from CD8+ T cells, enhancing their antigen-presenting capabilities [6][7][10]. Group 3: Implications for Clinical Practice - The study provides new insights into optimizing clinical treatment strategies for rectal cancer by elucidating the complex mechanisms of immune response during neoadjuvant therapy [4][10]. - The findings suggest that the quantity of IFNG+ CD8+ T cells and peripheral blood IFNG signaling could serve as markers for response to TNT [8].