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

Table 1 Representative prospective studies in spatial biology and precision oncology for colorectal cancer

Ref.	Phase	Population	Strategy	Endpoint	Status
Yao[38]	Prospective	LARC post-nCRT	ctDNA-guided adjuvant therapy decision	2-year DFS	Recruiting
University of Florida[39]	Phase II	ERC	Post-TNT ctDNA-guided watchful waiting vs surgery	Organ preservation rate	Recruiting
Mögele et al[37]	Prospective	LARC	ctDNA for prediction of pCR after nCRT	pCR prediction accuracy	Completed
Song et al[45]	Phase II	MSS ERC	Node-sparing short-course RT + CAPOX + PD-1/CTLA-4	pCR rate	Completed
Song et al[45]	Phase III	MSS LARC	Node-sparing short-course RT + CAPOX + tislelizumab vs CRT	3-year DFS	Completed
Bando et al[42]	Phase II	LARC	nCRT + nivolumab	pCR rate	Completed
Mo et al[51]	Prospective	Stage II-III CRC	ctDNA-MRD detection for recurrence risk stratification	2-year RFS	Completed
Tie et al[35] and Tie et al[36]	Phase II/III	LARC	ctDNA-guided adjuvant therapy de-escalation	Non-inferiority in RFS	Ongoing

LARC: Locally advanced rectal cancer; nCRT: Neoadjuvant chemoradiotherapy; ctDNA: Circulating tumor DNA; DFS: Disease-free survival; ERC: Early rectal cancer; TNT: Total neoadjuvant therapy; pCR: Pathological complete response; MSS: Microsatellite stable; RT: Radiotherapy; CAPOX: Capecitabine and oxaliplatin; PD-1: Programmed cell death protein 1; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; CRT: Chemoradiotherapy; CRC: Colorectal cancer; MRD: Minimal residual disease; RFS: Recurrence-free survival.

Table 2 Mechanisms and translational strategies for spatial biology-informed precision oncology in rectal cancer

Spatial phenotype	Biological characteristics	Immune features	Potential therapeutic targets	Clinical trial
Coordinate complete response (TRG1 + LRG1/ypN0)	Robust antitumor immunity; immune-mediated clearance; minimal residual disease	Enriched IFNG+ CD8+T; ACKR1+ EC cross-talk; low Treg/MDSC infiltration; low CAF activity	Immune checkpoint preservation; avoid overtreatment	Watch/wait protocols; de-escalation trials[35,36,39]
Nodal sanctuary phenotype (TRG1-2 + LRG4-5)	Primary tumor responds; nodal metastases persist; immunosuppressive nodal niche	Nodal Treg enrichment; exhausted T-cell phenotype; secreted phosphoprotein 1+ macrophages; fibrotic encapsulation	Immune checkpoint inhibitors; TGF-β inhibitors; nodal radiotherapy boost; lymph node-sparing RT	mRCAT-E; mRCAT-III; nodal boost trials[42,45]
Primary resistance (TRG4-5 + LRG1-2)	Primary tumor resistant; nodal clearance achieved; primary TME immunosuppression	SCAND1-mediated immune evasion; mtDNA metabolic reprogramming; CAF-enriched stroma; hypoxia	SCAND1 targeting; metabolic modulators; CAF reprogramming; anti-angiogenic agents	Combination IO; novel targeted therapy trials[11,12]
Coordinate resistance (TRG4-5 + LRG4-5)	Systemic resistance; both compartments refractory; poor prognosis	Clonal heterogeneity; multi-compartment immunosuppression; high mutational burden	Intensified systemic therapy; novel IO combinations; ctDNA-guided adaptive therapy	DYNAMIC-rectal; FOLFOXIRI-based intensification[35,36,39]

TRG: Tumor regression grade; LRG: Lymph node regression grade; ypN: Pathological lymph node stage; IFNG: Interferon-gamma; ACKR1: Atypical chemokine receptor 1; EC: Endothelial cell; Treg: Regulatory T cell; MDSC: Myeloid-derived suppressor cell; CAF: Cancer-associated fibroblast; TGF-β: Transforming growth factor-beta; RT: Radiotherapy; mRCAT: Node-sparing radiotherapy trial; TME: Tumor microenvironment; SCAND1: SCAN-domain-containing protein 1; mtDNA: Mitochondrial DNA; IO: Immunotherapy; ctDNA: Circulating tumor DNA; FOLFOXIRI: Fluorouracil, leucovorin, oxaliplatin, and irinotecan.