Current status of multiple markers in precision immunotherapy for colorectal cancer

Chao Liu; Ya Lan; Hong Wang; Yanqiao Zhang

doi:10.20892/j.issn.2095-3941.2025.0030

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Figure 1
MeC exhibits unique immune activation characteristics independent of MSI status. MeC, medullary carcinoma; MMR, mismatch repair; TILs, tumor-infiltrating lymphocytes; MSI-H, microsatellite instability-high; MSS, microsatellite stable.

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Table 1

Current research on biomarkers for precision immunotherapy in CRC

Biomarkers	Microsatellite status	Efficacy indicator	Detection method	Significance
TMB	MSS/MSI-H	OS/PFS	WES	High TMB is associated with better immunotherapy efficacy but is not sufficient for independent prediction^7,8.
POLE/POLD1 mutation	MSS	OS	WES	MSS CRC with POLE mutations show elevated TILs, upregulated PD-L1, and durable clinical benefits from ICB therapy⁹.
Epigenetic gene mutation	MSS	OS/PFS/ORR	WES	Studies showed that epigenetic mutations (e.g., ARID1A and KMT2C) had higher ORRs and improved PFS and OS with ICI treatment^10,11.
DDR gene mutation	MSS	NA	WES	DDR mutations in MSS-CRC are associated with enhanced immune activity, including more cytotoxic cell infiltration, alleviative CD8⁺ T-cell exhaustion, and elevated IFN-γ scores¹¹.
Immunoscore	MSS	OS/PFS	IHC	Higher immunoscores are associated with better prognosis, more active anti-tumor immune microenvironment, and potentially greater sensitivity to immunotherapy¹².
PD-L1	MSI-H	ORR	IHC	The KEYNOTE-016 and Checkmate 142 trials showed no link between tumor cell PD-L1 expression and immunotherapy response, but high PD-L1 expression on immune cells improved ORR⁹.
B2M; JAK1/2	MSI-H	NA	NGS	B2M and JAK1/2 mutations are more common in MSI-H CRC patients, and CRC patients carrying these mutations can still benefit from anti-PD-1 therapy¹³.
TILs	MSI-H	OS/PFS	IHC	Treatment response and survival benefits of dMMR/MSI CRC patients are significantly associated with high TILs infiltration⁶.
CD8⁺ MeTIL score	MSI-H	NA	MSP	Patients with MSI-H and abundant CD8⁺ TILs had the best overall survival, despite MSI-H having lower CD8⁺ MeTIL scores than the MSI-L/MSS groups¹⁵.
GEP	MSS/MSI-H	NA	NanoString	High T cell–inflamed GEP indicates enhanced T cell activity and potentially better immunotherapy efficacy^16,17.

TMB, tumor mutational burden; DDR, DNA damage response; TILs, tumor-Infiltrating lymphocytes; CD8⁺ MeTIL, DNA methylation-based signature of CD8⁺ tumor-infiltrating lymphocytes; GEP, gene expression profiles; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; WES, whole-exome sequencing; IHC, immunohistochemistry; NGS, next-generation sequencing; MSP, methylation-specific PCR.