Tumor-node response heterogeneity: Exploring the “spatial biology” of neoadjuvant therapy response in rectal cancer and its clinical implications

Abstract

Neoadjuvant chemoradiotherapy - the combination of chemotherapy and radiation therapy administered before surgery - followed by total mesorectal excision is the foundation of treatment for locally advanced rectal cancer. Pathological assessment of the primary tumor commonly uses tumor regression grading, which quantifies the extent of tumor response to treatment and provides prognostic value. However, a growing body of evidence reveals profound inter- and intra-patient heterogeneity in treatment response between the primary tumor and its associated lymph nodes. This review explores the concept of ‘spatial biology’ - the study of how distinct anatomical compartments within a patient, such as the primary tumor site and nodal basins, show unique biological behaviors and distinct responses to therapy. We will synthesize current evidence from single-cell and spatial transcriptomic studies, explore the dynamic remodeling of the tumor immune microenvironment at the primary site, and contrast this with the unique (and often discordant) response within lymph nodes that may serve as immunological sanctuaries for resistant clones. The combination of a novel lymph node regression grading system, which specifically assesses treatment response in lymph nodes, with traditional tumor regression grading is proposed here to more accurately reflect this spatial variation. We will critically appraise current evidence supporting the use of lymph node regression grading, discuss its limitations and difficulties for clinical implementation, and propose a framework for risk stratification informed by spatial biology to guide tailored adjuvant strategies. Finally, we will describe potential future research directions, including multi-omics spatial mapping, circulating tumor DNA integration, and novel clinical trial designs incorporating lymph node-sparing radiotherapy. This system acts as a foundation for individualized precision oncology in rectal cancer.

Keywords: Rectal cancer; Lymph node regression grade; Spatial biology; Tumor microenvironment; Precision oncology

Core Tip: This review article presents a spatial biology framework that explains why primary tumors and metastatic lymph nodes in locally advanced rectal cancer often respond differently to neoadjuvant chemoradiotherapy. Key points include clarifying the mechanisms of immune evasion and mitochondrial genome dynamics, and integrating tumor and lymph node regression grades to define spatial response phenotypes. The framework enhances prognostic stratification, as evident in the nodal sanctuary phenotype, and facilitates tailored therapeutic strategies through a translational roadmap that includes circulating tumor genetic material-guided therapy and lymph node-sparing radiotherapy trials. Ultimately, this approach aims to advance compartment-aware, biology-driven precision oncology in rectal cancer.