# The extracellular matrix in inflammation and cancer **Authors:** Wanting Zhang, Yuhang Xiang, Chen Lu, Fei Wang, He Ren, Hao Wu, Meisi Yan PMC · DOI: 10.1186/s43556-026-00415-6 · Molecular Biomedicine · 2026-03-06 ## TL;DR This paper reviews how the extracellular matrix influences immune cell behavior in inflammation and cancer, and how targeting it could improve cancer immunotherapy. ## Contribution The paper systematically outlines ECM constituents and their role in immune regulation, and explores therapeutic strategies targeting ECM-mediated immunosuppression. ## Key findings - ECM remodeling by cytokines and proteases shapes a tumor-supportive stroma. - Dysregulated ECM components interact with immune cell receptors to suppress immune function. - Targeting ECM-mediated immunosuppression may enhance cancer immunotherapy efficacy. ## Abstract The extracellular matrix (ECM) forms a dynamic structure around cells, providing environmental cues, mechanical support, and tissue protection. It is composed of fibrous proteins, glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. The molecular, physical, and mechanical properties of the ECM regulate the motility, survival, and function of immune cells. In most cancers, inflammatory cytokines and proteases—particularly matrix metalloproteinases(MMPs)—released within the immune-infiltrated inflammatory microenvironment can remodel the ECM. Cytokines such as tumor necrosis factor-α (TNF), interleukin, and transforming growth factor-beta (TGF-β) modulate the expression of various ECM molecules and promote host cell differentiation, thereby shaping a stroma conducive to tumor survival and metastasis. When ECM components become dysregulated, they act as ligands interacting with immune cell receptors, suppressing the function of specific immune cell subsets in the tumor microenvironment (TME), and activating downstream intracellular signaling pathways that are exploited by cancer cells to facilitate progression. This review systematically outlines key ECM constituents, molecular mediators of ECM remodeling, and their role in regulating immune cell behavior, including T cell exhaustion and macrophage polarization. It also elucidates the direct interactions between ECM and immune cells within inflammatory settings. Furthermore, we explore therapeutic strategies targeting ECM-mediated immunosuppression in solid tumors. This study highlights promising approaches to enhance the efficacy of cancer immunotherapy. ## Linked entities - **Proteins:** TNF (tumor necrosis factor), TGFB1 (transforming growth factor beta 1) - **Diseases:** cancer (MONDO:0004992) ## Full-text entities - **Genes:** ITGA5 (integrin subunit alpha 5) [NCBI Gene 3678] {aka CD49e, FNRA, VLA-5, VLA5A}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, BCAR1 (BCAR1 scaffold protein, Cas family member) [NCBI Gene 9564] {aka CAS, CAS1, CASS1, CRKAS, P130Cas}, Lair1 (leukocyte-associated Ig-like receptor 1) [NCBI Gene 52855] {aka 5133400O11Rik, D7Bwg0421e, Lair-1}, MMP14 (matrix metallopeptidase 14) [NCBI Gene 4323] {aka MMP-14, MMP-X1, MT-MMP, MT-MMP 1, MT1-MMP, MT1MMP}, MMP8 (matrix metallopeptidase 8) [NCBI Gene 4317] {aka CLG1, HNC, MMP-8, PMNL-CL}, APP (amyloid beta precursor protein) [NCBI Gene 351] {aka AAA, ABETA, ABPP, AD1, APPI, CTFgamma}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, ADAM17 (ADAM metallopeptidase domain 17) [NCBI Gene 6868] {aka ADAM18, CD156B, CSVP, HYPT16, NISBD, NISBD1}, GDF15 (growth differentiation factor 15) [NCBI Gene 9518] {aka GDF-15, HG, MIC-1, MIC1, NAG-1, PDF}, Aim2 (absent in melanoma 2) [NCBI Gene 383619] {aka Gm1313, Ifi210}, Cd44 (CD44 antigen) [NCBI Gene 12505] {aka HERMES, Ly-24, Pgp-1}, COL11A1 (collagen type XI alpha 1 chain) [NCBI Gene 1301] {aka CO11A1, COLL6, DFNA37, STL2}, hmp-1 (Alpha-catenin-like protein hmp-1;Vinculin) [NCBI Gene 179624], ZEB1 (zinc finger E-box binding homeobox 1) [NCBI Gene 6935] {aka AREB6, BZP, DELTAEF1, FECD6, NIL2A, PPCD3}, ITGA11 (integrin subunit alpha 11) [NCBI Gene 22801] {aka HsT18964}, PXN (paxillin) [NCBI Gene 5829], RYR2 (ryanodine receptor 2) [NCBI Gene 6262] {aka ARVC2, ARVD2, RYR-2, RyR, VACRDS, VTSIP}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Bgn (biglycan) [NCBI Gene 12111] {aka BG, DSPG1, PG-S1, PGI, SLRR1A}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 1493] {aka ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4}, CD276 (CD276 molecule) [NCBI Gene 80381] {aka 4Ig-B7-H3, B7-H3, B7H3, B7RP-2}, MMP3 (matrix metallopeptidase 3) [NCBI Gene 4314] {aka CHDS6, MMP-3, SL-1, STMY, STMY1, STR1}, STAB1 (stabilin 1) [NCBI Gene 23166] {aka CLEVER-1, FEEL-1, FEEL1, FELE-1, FEX1, HRFT}, CHI3L1 (chitinase 3 like 1) [NCBI Gene 1116] {aka ASRT7, CGP-39, GP-39, GP39, HC-gp39, HCGP-3P}, P4HA1 (prolyl 4-hydroxylase subunit alpha 1) [NCBI Gene 5033] {aka P4HA}, Il17a (interleukin 17A) [NCBI Gene 16171] {aka Ctla-8, Ctla8, IL-17, IL-17A, Il17}, IL22 (interleukin 22) [NCBI Gene 50616] {aka IL-21, IL-22, IL-D110, IL-TIF, ILTIF, TIFIL-23}, RAC1 (Rac family small GTPase 1) [NCBI Gene 5879] {aka MIG5, MRD48, Rac-1, TC-25, p21-Rac1}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) [NCBI Gene 5352] {aka BRKS2, LH2, TLH}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, Col18a1 (collagen, type XVIII, alpha 1) [NCBI Gene 12822], IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, PF4 (platelet factor 4) [NCBI Gene 5196] {aka CXCL4, PF-4, SCYB4}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, CD44 (CD44 molecule (IN blood group)) [NCBI Gene 960] {aka CDW44, CSPG8, ECM-III, ECMR-III, H-CAM, HCELL}, CCL21 (C-C motif chemokine ligand 21) [NCBI Gene 6366] {aka 6Ckine, CKb9, ECL, SCYA21, SLC, TCA4}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, TLR2 (toll like receptor 2) [NCBI Gene 7097] {aka CD282, TIL4}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, FGB (fibrinogen beta chain) [NCBI Gene 2244] {aka HEL-S-78p}, VCAN (versican) [NCBI Gene 1462] {aka CSPG2, ERVR, GHAP, PG-M, WGN, WGN1}, SRC (SRC proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 6714] {aka ASV, SRC1, THC6, c-SRC, p60-Src}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, PTK2 (protein tyrosine kinase 2) [NCBI Gene 5747] {aka FADK, FADK 1, FAK, FAK1, FRNK, PPP1R71}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, Tnc (tenascin C) [NCBI Gene 21923] {aka C130033P17Rik, Hxb, TN, TN-C, Ten, cytotactin}, Cd274 (CD274 antigen) [NCBI Gene 60533] {aka A530045L16Rik, B7h1, Pdcd1l1, Pdcd1lg1, Pdl1}, JUN (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3725] {aka AP-1, AP1, c-Jun, cJUN, p39}, PIEZO1 (piezo type mechanosensitive ion channel component 1 (Er blood group)) [NCBI Gene 9780] {aka DHS, ER, FAM38A, LMPH3, LMPHM6, Mib}, CCR2 (C-C motif chemokine receptor 2) [NCBI Gene 729230] {aka CC-CKR-2, CCR-2, CCR2A, CCR2B, CD192, CKR2}, SELPLG (selectin P ligand) [NCBI Gene 6404] {aka CD162, CLA, PSGL-1, PSGL1}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, FOS (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 2353] {aka AP-1, C-FOS, p55}, LOXL1 (lysyl oxidase like 1) [NCBI Gene 4016] {aka LOL, LOXL} - **Diseases:** colorectal cancer (MESH:D015179), leukemic (MESH:D007938), chronic lymphocytic leukemia (MESH:D015451), atherosclerosis (MESH:D050197), urothelial carcinoma (MESH:D014523), skin disease (MESH:D012871), pancreatic cancer (MESH:D010190), Helicobacter pylori (MESH:D016481), thyroid cancer metastasis (MESH:D013964), pancreatic tissue necrosis (MESH:D019283), tumorigenic (MESH:D002471), carcinogenic (MESH:D011230), HS (MESH:D017497), cirrhosis (MESH:D005355), malignant melanoma (MESH:D008545), RA (MESH:D001172), prostate cancer (MESH:D011471), urinary tract cancer (MESH:D014571), epithelial carcinoma (MESH:D009375), Metastasis (MESH:D009362), salivary adenoid cystic carcinoma (MESH:D003528), Chronic infections (MESH:D000088562), PDAC (MESH:D021441), fibrotic diseases (MESH:D004194), acute and chronic inflammation (MESH:D007249), osteosarcoma (MESH:D012516), ulcer (MESH:D014456), Hepatitis B (MESH:D006509), dECM (MESH:C535509), aortic aneurysms (MESH:D001014), rectal cancer (MESH:D012004), Hepatitis C (MESH:D019698), acidosis (MESH:D000138), acute pancreatitis (MESH:D010195), toxicity (MESH:D064420), hepatic fibrosis (MESH:D008103), synovitis (MESH:D013585), COVID-19 (MESH:D000086382), chronic viral hepatitis (MESH:D006525), calcification (MESH:D002114), cancer (MESH:D009369), IPF (MESH:D054990), lung cancer (MESH:D008175), infection (MESH:D007239), pulmonary fibrosis (MESH:D011658), LGG (MESH:D008228), CCA (MESH:D018281), ovarian and lung cancer (MESH:D010051), tumorigenesis (MESH:D063646), oncogenes (MESH:D000074723), chronic pulmonary inflammation (MESH:D011014), gastrointestinal nematode (MESH:D009349), thromboembolic (MESH:D013923), gastrointestinal cancers (MESH:D005770), Gastric cancer (MESH:D013274), lymph node metastasis (MESH:D008207), autoimmune diseases (MESH:D001327), TNBC (MESH:D064726), Inflammatory bowel disease (MESH:D015212), CaP (MESH:D002128) - **Chemicals:** oxygen (MESH:D010100), BAPN (MESH:D000629), defactinib (MESH:C584510), carboplatin (MESH:D016190), GAG (MESH:D006025), DOX (MESH:D004317), GC1008 (MESH:C560928), chondroitin sulfate (MESH:D002809), HA Hyaluronan (-), carbohydrate (MESH:D002241), polymer (MESH:D011108), Simtuzumab (MESH:C000613471), bivatuzumab (MESH:C479239), PTX (MESH:D017239), Losartan (MESH:D019808), LY2801653 (MESH:C586252), Nilotinib (MESH:C498826), dasatinib (MESH:D000069439), PL1 (MESH:D000077543), FOLFIRINOX (MESH:C000627770), galunisertib (MESH:C557799), atezolizumab (MESH:C000594389), glutamine (MESH:D005973), L (MESH:D007930), ATP (MESH:D000255), zymosan (MESH:D015054), ROS (MESH:D017382), HA (MESH:D006820), aldehydes (MESH:D000447), calcium (MESH:D002118), hydroxylysine (MESH:D006901), TIMPs (MESH:C003449), mertansine (MESH:D008453), lysine (MESH:D008239), gemcitabine (MESH:D000093542), Calcium phosphate (MESH:C020243) - **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Severe acute respiratory syndrome coronavirus 2 (no rank) [taxon 2697049], Caenorhabditis (genus) [taxon 6237] - **Cell lines:** Jurkat T — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_0065), HepG2 — Homo sapiens (Human), Hepatoblastoma, Cancer cell line (CVCL_0027), 4T1 — Mus musculus (Mouse), Malignant neoplasms of the mouse mammary gland, Cancer cell line (CVCL_0125), THP-1 — Cricetulus griseus (Chinese hamster), Spontaneously immortalized cell line (CVCL_JX40) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12963566/full.md ## Figures 5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12963566/full.md ## References 47 references — full list in the complete paper: https://tomesphere.com/paper/PMC12963566/full.md --- Source: https://tomesphere.com/paper/PMC12963566