Editorial: Impact of the Inflammatory Microenvironment on Immune Infiltration in Colorectal and Liver Cancers: Insights for New Immunotherapeutic Strategies

Yuchuan Jiang^*Kai Xiong

• Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, Nanchang, China

Colorectal cancer and liver cancer together account for a substantial and increasing global cancer burden[1, 2]. Over the past decade, immunotherapy has achieved meaningful gains across multiple malignancies, including these two diseases[3]. However, clinical benefit is tightly conditioned by the immunological phenotype of the tumor microenvironment (TME). Commonly used categories include immune-enriched (activation), fibrotic/immune-enriched (immune residence), fibrotic (immune suppression), and immune-depleted (immune exclusion) states[4]. To overcome primary and acquired resistance, combination regimens that pair immune checkpoint inhibitors (ICIs) with TME-remodeling agents have become a central strategy[5]. Inflammation drives the initiation and evolution of colorectal and liver cancers. Beyond mutagenesis, chronic low-grade inflammation nonspecifically activates T cells, promotes exhaustion and anergy, recruits and skews immunosuppressive cells, and ultimately establishes tumor immune tolerance [6, 7]. Clarifying how inflammatory cues enforce tolerance, and building prognostic models anchored in inflammation-linked immune indices, may improve outcomes and quality of life for patients with colorectal and liver cancers. This Research Topic brings together original studies and a systematic review that advance mechanistic insight and translational readiness across spatial pathology, epigenetics, niche mapping, and functional prognostics. Chen et al. introduce the tumor infiltration proportion within lymph nodes (TIPLN) as a pragmatic, pathology-embedded spatial biomarker for N1 colorectal cancer. Across training and validation cohorts, per‑patient maximal TIPLN independently predicted overall survival and, when incorporated into a nomogram, improved discrimination, reclassification, and net clinical benefit—operationalizing regional niche remodeling for postoperative risk stratification and prospective trial enrichment. Liang et al. delineate an epigenetic–immune escape axis in hepatocellular carcinoma centered on GINS1. Using transcriptomic, proteomic, and immunohistochemical evidence, they show GINS1 upregulation, site-specific methylation associations with survival, broad coupling to m6A regulators, and positive correlations with multiple inhibitory checkpoints, nominating GINS1 and its methylome as companion biomarkers and supporting epigenetic–checkpoint combinations in HCC. He et al. provide a decade-spanning bibliometric synthesis of the colorectal cancer TME, documenting rapid growth since 2019 and convergent hotspots in ICI therapeutics, CAF heterogeneity and macrophage polarization, intestinal microbiota, colorectal liver metastasis, drug resistance, and single-cell/spatial multi-omics. Their analysis identifies China and the United States as major collaboration hubs and underscores the need for higher research quality, standardization, and deeper international partnerships. Ma et al. integrate fourteen programmed cell death (PCD) pathways to derive a three‑gene signature—FABP4 as a risk gene and AQP8 and NAT1 as protective—that robustly stratifies prognosis across multiple cohorts and aligns with an "immune‑inflamed" versus "stroma‑dominant" niche dichotomy. Low‑risk tumors show greater infiltration by B cells, CD4+ and CD8+ T cells, NK cells, and M1 macrophages; reduced stromal and endothelial signals; higher predicted and observed ICI responsiveness; and greater sensitivity to first‑line chemotherapy. Functional assays further show that NAT1 overexpression augments apoptosis, reinforcing biological plausibility. Together, these studies outline a concise framework linking inflammation to niche states and clinical outcomes. Companion diagnostics should integrate spatial pathology (TIPLN, TLS maturation, immune topology, CAF/stroma/vascular scores), molecular markers (GINS1 expression and methylation, multi‑PCD scores), and dynamic readouts (ctDNA, circulating immune profiling, radiomics fused with spatial omics). Therapeutically, prioritize niche‑decompressing combinations—ICIs with anti‑TGF‑β or CSF1R blockade— with selective addition of LAG‑3/TIGIT inhibition; add epigenetic–ICI regimens for GINS1/methylation‑defined subsets; pair metabolic and vascular normalization with ICIs; and apply microbiome interventions, particularly for colorectal liver metastasis. Perioperative and neoadjuvant windows are opportune to reprogram niches and seed durable immune memory. Next steps include standardizing TIPLN and PCD cutoffs through multicenter, real‑world validation; deploying integrated single‑cell/spatial multi‑omics with harmonized digital pathology to reduce bias; testing causality in organoid–immune co‑cultures and humanized models; and designing trials stratified by spatial and molecular niche fingerprints, with biomarker‑guided monitoring to balance efficacy and toxicity— especially in cirrhosis and microbiome‑modulating contexts.