Converting cold to hot: Strategies to sensitize microsatellite-stable colorectal cancer to immunotherapy

Table 2 Selected clinical evidence for immunotherapy combination strategies in microsatellite-stable/proficient mismatch repair metastatic colorectal cancer

Combination strategy/regimen	Clinical setting (population)	Key outcomes	Predictors/caveats	Ref.
Pembrolizumab + mFOLFOX7 or FOLFIRI (KEYNOTE-651)	1 L/2 L advanced CRC (predominantly pMMR/MSS)	Safety acceptable; no clear signal beyond historical chemo in unselected MSS cohorts	Single-arm; chemotherapy confounds ORR; highlights need for biomarker enrichment	Gallois et al[57]; Kim et al[58]
Maintenance FP + bevacizumab ± atezolizumab (MODUL)	Post-induction maintenance in mCRC (unselected; largely MSS)	No significant PFS (HR = 0.92) or OS (HR = 0.94) improvement vs control	Negative phase II; subgroup signals require validation	Wang et al[59]
CAPOX + bevacizumab + pembrolizumab (FFCD1703-POCHI)	1 L pMMR/MSS mCRC with high TIL/Immunoscore	ORR = 73% (17% CR); DCR 100%; 12-month PFS 52%; 24-month OS 80%	Biomarker-enriched (high Immunoscore); confirm in larger/controlled studies	Yamaguchi et al[60]
Regorafenib + nivolumab (REGONIVO, phase Ib)	Refractory MSS mCRC (Japan)	ORR approximately 33%-36% in CRC cohort; median PFS approximately 7.9 months	Early-phase; later Western studies show lower activity; liver metastases may blunt benefit	Fukuoka et al[65]
Regorafenib + nivolumab (phase II)	Refractory MSS mCRC (multicenter United States)	ORR 7% (5/70 PR); median PFS 1.8 months; OS 11.9 months	All responders had no liver metastases	Fakih et al[66]
Fruquintinib + sintilimab	Refractory MSS mCRC (China phase II)	ORR 12.5%; DCR 76.4%; median PFS 4.1 months; OS 15.3 months	Liver mets: PFS 3.2 months vs 7.6 months; NLR/albumin/ECOG predictive	Zhang et al[68]
Regorafenib + ipilimumab + nivolumab	Refractory MSS mCRC (single-center phase I)	ORR 27.6%; median PFS 4.0 months; OS 20 months; non-liver mets ORR 36.4%	Responses largely confined to nonliver metastatic disease; dose-related skin/immune AEs	Xiao et al[69]; Fakih et al[70]
Atezolizumab + cobimetinib (IMblaze370)	Refractory mCRC (predominantly MSS; phase III)	No OS benefit vs regorafenib; ORR approximately 2%	Suggests MEK inhibition alone is insufficient; scheduling/partner choice critical	Eng et al[40]
Radiotherapy + ICI (various early-phase)	MSS mCRC; often liver-dominant disease	Clinical benefit inconsistent; abscopal responses uncommon	Dose/fractionation, target lesions, and systemic priming likely determinants	Yang et al[91]; Lee et al[92]; Nelson et al[93]; Hang et al[94]
Locoregional therapy + ICI (HIPEC/HAIC/TACE/SIRT; early-phase)	Liver or peritoneal metastases	Primarily early-phase/ongoing; rationale is in situ antigen release and myeloid reprogramming	Safety/sequence critical; endpoints include immune correlatives	Nelson et al[93]; Nevo et al[95]; Jiang et al[96]

CAPOX: Capecitabine + oxaliplatin; FP: Fluoropyrimidine; ICI: Immune checkpoint inhibitor; HIPEC: Hyperthermic intraperitoneal chemotherapy; HAIC: Hepatic arterial infusion chemotherapy; TACE: Transarterial chemoembolization; SIRT: Selective internal radiation therapy; mCRC: Metastatic colorectal cancer; MSS: Microsatellite-stable; pMMR: Mismatch repair-proficient; CRC: Colorectal cancer; TIL: Tumor-infiltrating lymphocyte; OS: Overall survival; PFS: Progression-free survival; CR: Complete response; DCR: Disease control rate; ORR: Objective response rate; HR: Hazard ratio; PR: Partial response; NLR: Neutrophil-to-lymphocyte ratio; ECOG: Eastern Cooperative Oncology Group; AE: Adverse event; MEK: Mitogen-activated protein kinase kinase.