# A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy **Authors:** Jia-Yin Chen, Yu-Ting Xue, Bin Lin, Xu-Yun Huang, Fei Lin, Dong-Ning Chen, Wan-Jin Zhang, Yong Wei, Xue-Yi Xue, Qing-Shui Zheng, Zhi-Bin Ke, Ning Xu PMC · DOI: 10.1038/s41419-026-08577-5 · 2026-03-19 ## TL;DR This study reveals a feedback loop involving prostate cancer cells and macrophages that drives cancer progression and resistance to radiotherapy. ## Contribution The study identifies a novel STAT1/lactate/NFκB1/MCP-1 feedback mechanism linking prostate cancer cells and macrophages. ## Key findings - STAT1 increases lactate production in prostate cancer cells. - Lactate activates macrophages to promote M2 polarization and MCP-1 secretion. - MCP-1 activates JAK/STAT1 in cancer cells, enhancing tumor progression and radioresistance. ## Abstract The resistance to radiotherapy of prostate cancer is driven by interactions within the tumor microenvironment, particularly between prostate cancer cells and tumor-associated macrophages, however the underlying mechanisms remain poorly understood. In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NFκB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1/lactate/NFκB1/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer. ## Linked entities - **Genes:** STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772], NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790], CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347], CCR2 (C-C motif chemokine receptor 2) [NCBI Gene 729230], jak (Janus kinase) [NCBI Gene 778659] - **Chemicals:** lactate (PubChem CID 61503) - **Diseases:** prostate cancer (MONDO:0005159) ## Full-text entities - **Genes:** Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, CD80 (CD80 molecule) [NCBI Gene 941] {aka B7, B7-1, B7.1, BB1, CD28LG, CD28LG1}, NQO1 (NAD(P)H quinone dehydrogenase 1) [NCBI Gene 1728] {aka DHQU, DIA4, DTD, NMOR1, NMORI, QR1}, CD68 (CD68 molecule) [NCBI Gene 968] {aka GP110, LAMP4, SCARD1}, CCR4 (C-C motif chemokine receptor 4) [NCBI Gene 1233] {aka CC-CKR-4, CD194, CKR4, CMKBR4, ChemR13, HGCN:14099}, Ldha (lactate dehydrogenase A) [NCBI Gene 16828] {aka Ldh1, Ldhm, l7R2}, HK2 (hexokinase 2) [NCBI Gene 3099] {aka HKII, HXK2}, PFKM (phosphofructokinase, muscle) [NCBI Gene 5213] {aka ATP-PFK, GSD7, PFK-1, PFK-A, PFK1, PFKA}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, SLC16A1 (solute carrier family 16 member 1) [NCBI Gene 6566] {aka HHF7, MCT, MCT1, MCT1D}, CREB1 (cAMP responsive element binding protein 1) [NCBI Gene 1385] {aka CREB, CREB-1}, CCR2 (C-C motif chemokine receptor 2) [NCBI Gene 729230] {aka CC-CKR-2, CCR-2, CCR2A, CCR2B, CD192, CKR2}, PKM (pyruvate kinase M1/2) [NCBI Gene 5315] {aka CTHBP, HEL-S-30, OIP3, PK3, PKM2, TCB}, PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) [NCBI Gene 5209] {aka IPFK2, PFK2, iPFK-2}, MYB (MYB proto-oncogene, transcription factor) [NCBI Gene 4602] {aka Cmyb, c-myb, c-myb_CDS, efg}, Ccr2 (C-C motif chemokine receptor 2) [NCBI Gene 12772] {aka Cc-ckr-2, Ccr2a, Ccr2b, Ckr2, Ckr2a, Ckr2b}, Hk2 (hexokinase 2) [NCBI Gene 15277] {aka HKII}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, ZEB1 (zinc finger E-box binding homeobox 1) [NCBI Gene 6935] {aka AREB6, BZP, DELTAEF1, FECD6, NIL2A, PPCD3}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, CCL2 (C-C motif chemokine ligand 2) [NCBI Gene 6347] {aka GDCF-2, HC11, HSMCR30, MCAF, MCP-1, MCP1}, Cd163 (CD163 antigen) [NCBI Gene 93671] {aka CD163v2, CD163v3}, RBM4 (RNA binding motif protein 4) [NCBI Gene 5936] {aka LARK, RBM4A, ZCCHC21, ZCRB3A}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, POTEF (POTE ankyrin domain family member F) [NCBI Gene 728378] {aka A26C1B, POTE2alpha, POTEACTIN}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Pfkm (phosphofructokinase, muscle) [NCBI Gene 18642] {aka ATP-PFK, PFK-A, PFK-M, Pfk-4, Pfk4, Pfka}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CCL17 (C-C motif chemokine ligand 17) [NCBI Gene 6361] {aka A-152E5.3, ABCD-2, SCYA17, TARC}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, SLC2A1 (solute carrier family 2 member 1) [NCBI Gene 6513] {aka CSE, DYT17, DYT18, DYT9, EIG12, GLUT}, PTP4A3 (protein tyrosine phosphatase 4A3) [NCBI Gene 11156] {aka PRL-3, PRL-R, PRL3}, CXCL9 (C-X-C motif chemokine ligand 9) [NCBI Gene 4283] {aka CMK, Humig, MIG, SCYB9, crg-10}, Stat1 (signal transducer and activator of transcription 1) [NCBI Gene 20846] {aka 2010005J02Rik}, SRSF10 (serine and arginine rich splicing factor 10) [NCBI Gene 10772] {aka FUSIP1, FUSIP2, NSSR, PPP1R149, SFRS13, SFRS13A}, 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}, NFKBIA (NFKB inhibitor alpha) [NCBI Gene 4792] {aka EDAID2, IKBA, MAD-3, NFKBI}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, Csf1 (colony stimulating factor 1 (macrophage)) [NCBI Gene 12977] {aka BAP025, Csfm, MCSF, Mhdabap25, PG-M-CSF, op}, H2ax (H2A.X variant histone) [NCBI Gene 15270] {aka H2A.X, H2afx, Hist5-2ax, gammaH2ax}, HK1 (hexokinase 1) [NCBI Gene 3098] {aka CNSHA5, HK, HK1-ta, HK1-tb, HK1-tc, HKD}, mct1 (modifier of curly tail 1) [NCBI Gene 17236], LDHA (lactate dehydrogenase A) [NCBI Gene 3939] {aka GSD11, HEL-S-133P, LDHM, PIG19}, CMA1 (chymase 1) [NCBI Gene 1215] {aka CYH, MCT1, chymase}, RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65} - **Diseases:** OCR (MESH:D000860), cancers (MESH:D009369), pituitary adenoma (MESH:D010911), squamous cell carcinoma (MESH:D002294), inflammation (MESH:D007249), breast cancer (MESH:D001943), PCa (MESH:D011471), leukemia (MESH:D007938), lung cancer (MESH:D008175), tumorigenesis (MESH:D063646), pancreatic ductal adenocarcinoma (MESH:D021441), PDO (MESH:C536408), multiple myeloma (MESH:D009101), colorectal cancer (MESH:D015179), head and neck squamous cancer (MESH:D006258), rheumatoid arthritis (MESH:D001172), BMDMs (MESH:D001855), tumorigenic (MESH:D002471), CRPC (MESH:D064129), hepatocellular carcinoma (MESH:D006528), cervical cancer (MESH:D002583), BPH (MESH:D011470) - **Chemicals:** DMSO (MESH:D004121), penicillin (MESH:D010406), GSH (MESH:D005978), enzalutamide (MESH:C540278), formaldehyde (MESH:D005557), JSH-23 (MESH:C549066), Paraffin (MESH:D010232), AZD3965 (MESH:C000592351), water (MESH:D014867), BCA (MESH:C047117), Glucose (MESH:D005947), puromycin (MESH:D011691), Ruxolitinib (MESH:C540383), CO2 (MESH:D002245), hematoxylin (MESH:D006416), adenosine triphosphate (MESH:D000255), ethanol (MESH:D000431), crystal violet (MESH:D005840), Triton X-100 (MESH:D017830), oxygen (MESH:D010100), INCB8761 (MESH:C000620181), LA (MESH:D019344), Lipofectamine 2000 (MESH:C086724), citric acid (MESH:D019343), streptomycin (MESH:D013307), 2-DG (MESH:D003847), polyvinylidene fluoride (MESH:C024865), Agarose (MESH:D012685), 2Q-S (-), biotin (MESH:D001710), PMA (MESH:D013755), xylene (MESH:D014992), paraformaldehyde (MESH:C003043), DAPI (MESH:C007293), SDS (MESH:D012967), GSK2837808A (MESH:C000612070) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** HTX1927 — Homo sapiens (Human), Hunter syndrome, Finite cell line (CVCL_W659), CL-0198 — Homo sapiens (Human), Transformed cell line (CVCL_K463), C4-2 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_4782), PC-3R — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_C0QS), THP-1 — Homo sapiens (Human), Childhood acute monocytic leukemia, Cancer cell line (CVCL_0006), DU145 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0105), PC-3 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0035), C4-2B — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_4784), XF24 — Xenopus laevis (African clawed frog), Spontaneously immortalized cell line (CVCL_6E64), CL-0075 — Homo sapiens (Human), Finite cell line (CVCL_7277), M0 — Homo sapiens (Human), Familial hypertrophic cardiomyopathy type 26, Induced pluripotent stem cell (CVCL_A6XE), PC-3S — Homo sapiens (Human), Prostate carcinoma, Transformed cell line (CVCL_B7JD), CL-0004 — Homo sapiens (Human), Finite cell line (CVCL_H555), CL-0143 — Homo sapiens (Human), Trisomy 18, Finite cell line (CVCL_X226), CL-0185 — Homo sapiens (Human), Transformed cell line (CVCL_K450), c57BL/6J — Mus musculus (Mouse), Transformed cell line (CVCL_C0MW), 22RV1 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_1045), TCH-C361 — Homo sapiens (Human), Hyperlipoproteinemia, type IIa, Finite cell line (CVCL_V828), -N — Homo sapiens (Human), Finite cell line (CVCL_UZ57), 293 T — Homo sapiens (Human), Transformed cell line (CVCL_0063), CL-0200 — Homo sapiens (Human), Transformed cell line (CVCL_K465), LNCaP — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0395), HTX1928 — Homo sapiens (Human), Hunter syndrome, Finite cell line (CVCL_W660), CL-0005 — Homo sapiens (Human), Transformed cell line (CVCL_K289), RWPE-1 — Homo sapiens (Human), Transformed cell line (CVCL_3791), BALB/c — Mus musculus (Mouse), Spontaneously immortalized cell line (CVCL_0184), RM-1 — Mus musculus (Mouse), Carcinoma of the mouse prostate gland, Cancer cell line (CVCL_B459), S2C — Canis lupus familiaris (Dog), Canine mastocytoma, Cancer cell line (CVCL_1R44) ## Figures 8 figures with captions in the complete paper: https://tomesphere.com/paper/PMC13018544/full.md --- Source: https://tomesphere.com/paper/PMC13018544