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

Table 1 Major immunobiological barriers to immune checkpoint inhibition in microsatellite-stable/proficient mismatch repair colorectal cancer and actionable therapeutic opportunities

Immune barrier/feature	Mechanistic basis	Representative readouts/contexts	Actionable strategies
Low immunogenicity and weak antigen presentation	Low mutation load (MSS/Low TMB); impaired APC priming; HLA/B2M loss; IFN-JAK/STAT defects	Low TMB; low IFN-γ/CXCL9-CXCL10; MHC-I downregulation	Chemo/RT priming; STING/TLR agonists; epigenetic priming; vaccines/neoantigen approaches[13-15,25]
T cell exclusion by stromal/TGF-β programs	CAF-derived TGF-β; dense ECM; reduced trafficking/retention immuneexcluded phenotype	CMS4/stromal signature; high TGF-β; desmoplasia	TGF-β blockade/traps; CAF/ECM modulation; CXCR4 blockade; vessel normalization[27,28]
Oncogenic signaling-driven immune escape	KRAS/BRAF/MAPK or WNT/β-catenin suppress antigen presentation/chemokines and promote myeloid recruitment	RAS/BRAF mutations; MAPK/WNT activation signatures	Targeted therapy to reprogram TME (e.g., BRAF/MEK/EGFR); rational combinations with ICI[15,26]
Myeloid-dominant suppression (TAM/MDSC)	VEGF/CSF1/IL-8 axis; MDSC expansion; TAM M2 polarization; arginase/ROS-mediated T-cell suppression	High MDSC/TAM signatures; high NLR; VEGF-high tumors	Anti-VEGF/VEGFR TKIs; CSF1R/CXCR1/CXCR2 inhibition; CD47/SIRPα blockade (investigational)[10,16,19]
Checkpoint redundancy and T cell exhaustion	Co-expression of PD-1/PD-L1 with CTLA-4/LAG-3/TIGIT/TIM-3 dysfunctional CD8 pool	Exhaustion signatures; multiple checkpoints on TILs	Dual/next-gen checkpoint blockade; costimulatory agonists; intratumoral delivery[10,14]
Immunometabolic suppression	Hypoxia, lactate; adenosine (CD39/CD73); tryptophan catabolism (IDO/TDO); nutrient competition	High CD73; hypoxia markers; kynurenine/adenosine signatures	A2A/CD73 axis inhibitors; metabolic modulation; normalization of hypoxia/vasculature[35,36]
Microbiome-driven immune modulation	Dysbiosis (e.g., Fusobacterium) shapes myeloid programs and alters T cell function via microbial metabolites	Stool metagenomics; Fusobacterium abundance; bile acid/SCFA profiles	Diet/probiotic/FMT strategies; antibiotic stewardship; microbiome-informed stratification[33,34]
Metastatic niche effects (especially liver)	Hepatic tolerogenic myeloid cells; sequestration/deletion of activated T cells systemic suppression	Presence of liver metastases; low intrahepatic CD8 density	Liver-directed RT/SIRT/TACE + ICI; consider liver metastasis status in trial design[45,66,70]

TGF-β: Transforming growth factor-β; MDSC: Myeloid-derived suppressor cell; TAM: Tumor-associated macrophage; MSS: Microsatellite stable; TMB: Tumor mutational burden; APC: Antigen-presenting cell; B2M: Β2-microglobulin; HLA: Human leukocyte antigen; JAK/STAT: Janus kinase/signal transducer and activator of transcription; IFN: Interferon; CAF: Cancer-associated fibroblast; ECM: Extracellular matrix; MAPK: Mitogen-activated protein kinase; VEGF: Vascular endothelial growth factor; IL: Interleukin; CSF: Colony stimulating factor; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; ROS: Reactive oxygen species; CTLA-4: Cytotoxic T-lymphocyte-associated protein-4; LAG-3: Lymphocyte activation gene-3; TIGIT: T cell immunoglobulin and ITIM domain; CD: Cluster of differentiation; TIM-3: T cell immunoglobulin and mucin domain-containing protein 3; MHC: Major histocompatibility complex; CMS: Consensus molecular subtype; NLR: Neutrophil-to-lymphocyte ratio; TIL: Tumor-infiltrating lymphocyte; SCFA: Short-chain fatty acid; RT: Radiotherapy; STING: Stimulator of interferon genes; TLR: Toll like receptor; TME: Tumor microenvironment; MEK: Mitogen-activated protein kinase kinase; EGFR: Epidermal growth factor receptor; ICI: Immune checkpoint inhibitor; VEGFR: Vascular endothelial growth factor receptor; TKI: Tyrosine kinase inhibitor; SIRPα: Signal regulatory protein alpha; FMT: Fecal microbiota transplantation; SIRT: Selective internal radiation therapy; TACE: Transarterial chemoembolization.