(Press-News.org) Chronic inflammation is both a driver and suppressor of cancer depending on context. Key players—NF-κB, IL-6, STAT3, TAMs, MDSCs, and Tregs—orchestrate a tumor-permissive microenvironment. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionized treatment, but responses remain heterogeneous. This review examines mechanisms of inflammation-driven cancer, translational efforts targeting inflammatory pathways, and clinical strategies integrating immunotherapy with anti-inflammatory agents and biomarkers. Emerging technologies—AI, microbiome modulation, single-cell omics, and gene editing—promise to refine precision therapy and overcome resistance.
Introduction
Since Virchow's 19th-century observation, inflammation has been validated as a hallmark of cancer. Up to 20% of cancers are linked to chronic infections, autoimmunity, or environmental exposures. Inflammation drives all stages of tumorigenesis and modulates therapeutic response. This review synthesizes mechanistic, translational, and clinical advances in the cancer–inflammation axis.
Mechanistic Insights
Signaling Pathways: NF-κB and STAT3 promote survival, angiogenesis, and immunosuppression. COX-2/PGE2 drives proliferation and MDSC recruitment.
Immune Cells: TAMs (M2-polarized), MDSCs, Tregs, and N2 neutrophils suppress anti-tumor immunity. Single-cell analyses reveal heterogeneity and therapeutic targets.
Additional Pathways: NLRP3 inflammasome and epigenetic modifications perpetuate inflammatory cycles.
Cancer-Specific Examples:
CRC: Dysbiosis, NF-κB/STAT3 activation, NLRP3 correlates with poor prognosis.
Lung Cancer: Tobacco/air pollution trigger COX-2/PGE2 and IL-6/STAT3; KRAS mutations amplify immunosuppression.
Breast Cancer: Obesity-associated inflammation drives MDSC/Treg accumulation; CRP predicts neoadjuvant response.
Immunotherapy and Inflammation
Checkpoint Inhibitors: Anti-PD-1/PD-L1/CTLA-4 yield 20–40% response rates; elevated IL-6 predicts resistance. LAG-3 blockade (relatlimab) approved 2024.
CAR-T: Effective in hematologic malignancies; solid tumors limited by TME. CRISPR-edited CAR-T cells show improved persistence in inflammatory TME.
Vaccines & Oncolytic Viruses: Personalized neoantigen vaccines and talimogene laherparepvec under investigation; combination with anti-inflammatory agents being explored.
TILs: Efficacy in melanoma; CRISPR enhancement in development.
Emerging Therapies: BiTEs and ADCs target inflammatory markers for precise delivery.
Translational Advances
Drug Repurposing: Aspirin reduces CRC/metastasis risk; COX-2 inhibitors in FAP; statins under investigation.
Cytokine Targeting: Tocilizumab (anti-IL-6R), siltuximab (anti-IL-6), and infliximab (anti-TNF) in trials; 2025 studies combine IL-6 blockade with ICIs in pancreatic cancer.
NF-κB/STAT3 Inhibition: Bortezomib (proteasome inhibitor) suppresses NF-κB; novel STAT3 inhibitors reduce MDSCs preclinically.
Preclinical Models: Humanized mice; multi-omics; 2024 single-cell studies reveal spatial inflammatory niches.
Nanomedicine: Lipid nanoparticles reprogramming TAMs to M1 phenotype in breast cancer models.
Clinical Strategies & Biomarkers
Inflammatory Biomarkers: CRP, IL-6, NLR, and PIV (pan-immune-inflammation value) predict prognosis and ICI response.
Predictive Biomarkers: PD-L1 IHC, TMB, MSI; emerging ctDNA and microbiome signatures.
Combination Approaches: ICIs + aspirin, VEGF inhibitors, chemotherapy, or radiation; 2024 CRC trials combine ICIs with microbiome modulators.
irAE Management: Corticosteroids, TNF inhibitors; sCD25 predicts risk.
Personalized Medicine: AI-driven multi-omic models for patient stratification and real-time treatment adjustment.
Future Perspectives
Microbiome: Bifidobacterium, Akkermansia correlate with ICI response; FMT and CRISPR-based editing under investigation.
AI & Machine Learning: Predicting prognosis and CAR-T resistance; 2024 Stanford model integrates imaging and text data.
Gene Editing: CRISPR-Cas9 editing of exhaustion genes in CAR-T cells; RNA editing for reversible modulation.
Single-Cell & Spatial Omics: Identifying MDSC clusters and resistance mechanisms; integration with AI for dynamic TME mapping.
Nanotechnology & Liquid Biopsies: Nanoprobe TME monitoring; ctDNA-based inflammatory signatures for noninvasive response prediction.
Emerging Opportunities: ADC-delivered anti-inflammatory payloads; rational combination therapy targeting parallel pathways (NF-κB + STAT3); germline pharmacogenomics for personalized anti-inflammatory treatment.
Conclusions
Chronic inflammation drives tumorigenesis, immune evasion, and therapy resistance. Integrating inflammation-targeting strategies with immunotherapy and biomarker-guided approaches offers a path to personalized cancer care. Advances in microbiome modulation, AI, gene editing, and single-cell technologies position the field for transformative progress.
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