Integrated Multi-Time-Point ¹⁸F-FAPI PET/CT and Immune Histopathology for Predicting Pathological Complete Response in Microsatellite-Stable Locally Advanced Rectal Cancer Treated With Neoadjuvant Radiotherapy, Chemotherapy, and Immunotherapy.

Abstract

Predicting pathological complete response (pCR) after neoadjuvant short-course radiotherapy combined with immunotherapy and chemotherapy remains challenging in microsatellite-stable (MSS) locally advanced rectal cancer. In this prospective exploratory study (ClinicalTrials.gov identifier: NCT06608537), 49 patients received short-course radiotherapy followed by sintilimab plus CAPOX and subsequently underwent radical surgery. We investigated whether treatment response could be better characterized by integrating two complementary biological dimensions: baseline immune organization and treatment-related stromal remodeling captured by multi-time-point ¹ ⁸F-FAPI PET/CT. The pCR rate was 49.0% (24/49), and serial ¹ ⁸F-FAPI imaging revealed distinct stromal kinetic patterns between response groups. Integration of intratumoral tertiary lymphoid structure (iTLS) count, B-cell density, preoperative tumor-to-iliacus muscle ratio (TIMR) at 30 min, and the delayed TIMR retention index from 90 to 120 min (RI₃₄) yielded a four-variable model with a mean AUC of 0.874 in repeated nested cross-validation. Complementary preclinical experiments provided functional support for a CAF-TGFβ-B-cell/TLS axis linking stromal regulation, immune organization, and treatment resistance. These findings highlight the complementary value of spatial immune organization and dynamic FAPI-defined stromal kinetics and provide a biologically informed framework for post-neoadjuvant, preoperative response stratification, pending prospective multicenter validation.