Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was studied?
This original study investigated how a food-derived commensal bacterium, Lactiplantibacillus plantarum IMB19 (LpIMB19), enhances antitumor immunity by reprogramming tumor macrophages toward inflammatory phenotypes that exert lipocalin-2 iron sequestration in tumors. The authors used syngeneic melanoma, breast, and renal mouse models and a humanized xenograft bladder cancer model to test live and heat-killed LpIMB19 as well as its purified capsular rhamnose-rich heteropolysaccharide (RHP). Mechanistically, RHP ligates TLR2 on tumor-associated macrophages, boosting cytotoxic CD8⁺ T-cell responses and triggering nutritional immunity: macrophages secrete lipocalin-2 (LCN2) to capture siderophore-bound iron and upregulate ferritin to store iron intracellularly, collectively depriving nearby tumor cells of bioavailable iron. The work also shows additive benefit with anti-PD-L1 therapy, TCR clonal expansions in CD8⁺ tumor-infiltrating lymphocytes, and iron-handling rewiring in macrophages visualized by gene expression and functional assays.
Who was studied?
Multiple murine cancer models were used, including B16F10 melanoma, EMT-6 breast carcinoma, and orthotopic Renca renal tumors, with interventions delivered by oral LpIMB19 or intraperitoneal RHP. The study further humanized NOD-SCID mice with peripheral blood mononuclear cells and implanted patient-derived bladder cancer organoids to assess translation. Genetic tools included macrophage depletion (Cd11bDTR), Tlr2⁻/⁻ and Lcn2⁻/⁻ macrophage transfers, and LysMCre-driven ferroportin ablation to dissect pathway dependence. Across models, macrophages and CD8⁺ T cells in tumors and draining lymph nodes were phenotyped by flow cytometry, single-cell RNA-seq, bulk RNA-seq, and TCRβ sequencing, with iron flux tracked using SiRhoNox and ferritin immunoblotting.
Most Important Findings
| Critical point | Details |
|---|---|
| LpIMB19/RHP suppresses tumor growth and boosts survival | In B16F10 melanoma and other models, both live and heat-killed LpIMB19 reduced tumor burden; RHP alone recapitulated suppression, and co-therapy with anti-PD-L1 showed additive control and increased IFNγ⁺/TNF⁺ CD8⁺ TILs with reduced Lag3 expression. |
| Macrophage TLR2 is the principal sensor | RHP engages TLR2, not TLR4; macrophage activation (↑iNOS2, ↑CD86, ↑MHC I) and CD8⁺ priming were blunted with Tlr2 deficiency, establishing TLR2-dependent innate activation upstream of CD8⁺ responses. |
| Lipocalin-2–driven iron capture and ferritin storage | Gene-set enrichment highlighted iron sequestration pathways; macrophages upregulated Lcn2 and Fth1, secreted LCN2, and increased ferritin. Intratumoral macrophages accumulated iron, while tumor cells were iron-depleted in competition assays. |
| LCN2 is required for antitumor effect | In Cd11bDTR transfer experiments, Lcn2⁻/⁻ macrophages abrogated LpIMB19/RHP tumor control, failed to increase macrophage iron uptake, and reduced tumor apoptosis, establishing LCN2 as an effector of nutritional immunity. |
| Ferroportin loss does not add benefit | Macrophage-specific ferroportin deletion (Fpn^F/F LysMCre) did not enhance LpIMB19 efficacy or change steady-state intratumoral macrophage iron, indicating iron capture via LCN2, not export blockade, is primary. |
| Durable CD8⁺ T-cell cytotoxicity and clonal remodeling | scRNA-seq and TCRβ-seq showed more effector/memory CD8⁺ cells, reduced exhaustion, higher cytotoxic gene expression, and expanded dominant clonotypes, suggesting epitope broadening and clonal replacement dynamics. |
| Human relevance | In a PBMC-humanized bladder organoid xenograft, LpIMB19 and RHP reduced tumor mass and increased human IFNγ⁺ CD8⁺ T cells; macrophage signature orthologs stratified TCGA survival and improved PD-L1 response prediction with TMB. |
Key implications
For primary regulatory impacts, these data position macrophage-mediated nutritional immunity, especially lipocalin-2 iron sequestration in tumors, as an actionable safety and performance endpoint. Certification requirements for HTMC could include validated LCN2 induction, ferritin upregulation, and TLR2-dependent assays under tumor-mimetic conditions. Industry applications span probiotic oncobiotics, iron-chelation adjuncts, and PD-(L)1 combinations. Research gaps include human dose-response, microbiome variability, and off-tumor iron effects. Practical recommendations prioritize standardized iron-flux biomarkers, macrophage activation panels, and co-therapy compatibility testing.
Citation
Sharma G, Sharma A, Kim I, et al. A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron. Nature Immunology. 2024;25:790-801. doi:10.1038/s41590-024-01816-x
