This review synthesizes established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity and outlines an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Abstract
Androgen receptor signaling inhibitors (ARSIs) have transformed the treatment of advanced prostate cancer, yet durable responses are limited by the emergence of therapy-resistant disease states, including neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC). Lineage plasticity has traditionally been studied from a tumor-cell-intrinsic perspective, but single-cell and spatial studies increasingly indicate that the tumor microenvironment, particularly tumor-associated macrophages (TAMs), may influence tumor-cell state transitions, immune exclusion, and therapeutic resistance. In this review, we synthesize established and emerging evidence linking TAM heterogeneity to prostate cancer lineage plasticity. We first summarize independently supported myeloid programs, including SPP1+/TREM2+ macrophage states and TAM-derived pathways such as IL-6/STAT3, TGF-beta, NF-kappaB, CXCL12/CXCR4, and adenosine signaling. We then discuss PLAC8+ TAMs, TNFAIP8L2, and PLAC8+ TAM/CXCL12+ iCAF/CD8+ TRM spatial aggregates as an emerging, hypothesis-generating framework that may be associated with ARSI-induced DNPC-like remodeling. Importantly, we explicitly distinguish spatial and transcriptomic associations from experimentally proven causal mechanisms. The proposed TNFAIP8L2-integrin/PI3K-Akt/beta-catenin/FOSL1-HMGA1 cascade is therefore presented as a working model that requires direct biochemical, genetic, and in vivo validation. Finally, we outline an evidence-aware translational roadmap for TAM-directed therapy, emphasizing independent cohort validation, protein-level spatial confirmation, functional perturbation, and biomarker-guided clinical testing.
Prostate cancer is a hormone-driven malignancy, but its clinical behavior cannot be explained by androgen receptor (AR) signaling alone. Single-cell and spatial omics are redefining prostate cancer as an evolving metabolic-immune ecosystem in which malignant epithelial states, stromal niches, myeloid programs, T-cell exclusion, vascular remodeling, and treatment-imposed selection pressures jointly shape progression and resistance. These technologies have resolved the normal prostate epithelial hierarchy, pre-existing castration-resistant-like cells, basal-like, club-like, and hillock-like programs, neuroendocrine transformation states, immunosuppressive macrophage populations, fibroblast states, and spatial neighborhoods that are difficult to detect by bulk sequencing. Treatment-associated changes have been characterized most directly in androgen-axis and immune contexts, whereas evidence related to taxanes, DNA damage response (DDR)-targeted therapy, and radioligand therapy remains emerging or hypothesis-generating. This review synthesizes single-cell and spatial omics evidence for metabolic-immune ecosystems in prostate cancer, emphasizing the transition from androgen dependence to castration resistance, lineage plasticity, metastatic niche adaptation, and therapy resistance. We argue that the next translational step is not simply to catalog additional cell types, but to connect longitudinal cell-state maps, spatially resolved metabolic dependencies, immune-neighborhood biomarkers, and mechanism-matched combination therapies.
This review consolidates emerging evidence that positions cell competition as a critical regulator of clonal dynamics within the breast cancer TME and identifies competitive cellular fitness as a central and targetable driver of therapeutic resistance and tumor recurrence in breast cancer.
Esha Pal, Sovan Chakraborty, A. Guha· Frontiers in Oncology· 0 citations
Despite considerable progress in elucidating mechanisms leading to castration-resistant prostate cancer (CRPC), insight into the early stages of prostate cancer initiation and progression remains limited. Genomic drivers of prostate cancer initiation have been defined through patient tumor sequencing, but the subsequent events responsible for local tissue invasion are poorly understood. Here we leverage a well-studied genetically engineered mouse prostate cancer model (Hi-Myc) that, based on robust and reproducible kinetics for transitioning from pre-invasive prostatic intraepithelial neoplasia (PIN) to invasive prostate adenocarcinoma (PCa), provides an ideal system to systematically address this question using single-cell analysis. Surprisingly, the transcriptomic profiles of early PIN lesions are indistinguishable from those of late-stage, highly invasive tumor cells, suggesting that MYC activation at the PIN stage establishes a transcriptional program that is fully capable of driving invasion but is restrained by the local tumor microenvironment (TME). Indeed, we find that progression to PCa is associated with progressive infiltration of IL-1β+ tumor-infiltrating macrophages at the PIN stage that, based on immunodepletion and cytokine neutralization experiments, are required for the PIN-to-PCa transition. Mechanistically, IL-1β from macrophages acts directly on prostate fibroblasts, leading to the release of IL-6, which drives invasion by activating IL-6R in tumor cells. Collectively, these findings identify a pro-tumorigenic IL-1β/IL-6 signaling circuit mediated through local macrophages and fibroblasts that unleashes the full oncogenic potential of a cancer driver (MYC) activated at the PIN stage. We also find evidence of this circuit in other (non-MYC-driven) prostate cancer models as well as human prostate and lung adenocarcinoma, with implications for TME-specific targeted therapeutics in early-stage disease.
Young Sun Lee, Jimmy L. Zhao, Agnieszka Chryplewicz et al.· bioRxiv· 0 citations
Lung cancer is the deadliest pulmonary malignancy, driven in part by immune evasion and limited treatment options. Among key immunoregulatory players, tumor-associated macrophages (TAMs) promote angiogenesis, immunosuppression, and metastasis via M2-like polarization. MARCKS (myristoylated alanine-rich C-kinase substrate), an oncogenic regulator, is highly expressed in both tumor cells and TAMs, with elevated levels linked to cancer progression. However, its role in TAM-mediated immune modulation remains poorly understood.
We analyzed single-cell RNA sequencing data from lung cancer patients. TAMs were stratified into MARCKS-proficient (MARCKS+) and -deficient (MARCKS⁻) subsets. Differential expression and pathway enrichment analyses were performed, and CellChat was used to assess intercellular communication.
MARCKS+ TAMs were enriched for immunosuppressive pathways, including IL-10 family cytokines, efferocytosis, and CD163-associated M2 programs. CCR5-related pathways implicated proliferative and migratory signaling, while suppression of T cell immunity suggested immune evasion. CellChat analysis showed significantly increased communication by MARCKS+ TAMs. Key outgoing ligands included SPP1, CCL, MIF, VEGF, TNF, and TGF-β, whereas incoming signals featured TGF-β, TNF, ITGB2, and SPP1. MARCKS+ TAMs uniquely received TGF-β, a potent M2 inducer, and secreted SPP1, linked to metastasis, therapy resistance, and fibroblast differentiation into cancer-associated fibroblasts. MIF—CD74—CXCR4 signaling further contributed to Treg recruitment and NK cell suppression.
MARCKS+ TAMs amplify immunosuppressive signaling that enhances macrophage polarization, immune evasion, and tumor-stromal crosstalk. By driving TGF-β- and SPP1-mediated interactions with tumor and immune compartments, MARCKS emerges as a key regulator of TAM-driven immunosuppression and a potential therapeutic target in lung cancer.
This work was supported by the NIH grant R01HL146802, the UCOP TRDRP grant T32IR5347, and the DoD PRMRP grant W81XWH2110086 (#PR202411).
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
J. Berton, Johnny Vang, Anjolie Doan et al.· Journal of Immunology· 0 citations
Bladder cancer is characterized by a highly dynamic tumor microenvironment (TME) that critically influences tumor progression, immune evasion, and therapeutic responsiveness. Among the immune populations in the TME, regulatory T cells (Tregs) play a central role in maintaining immune tolerance but also suppress effective antitumor immunity. Increasing evidence suggests that Tregs accumulate in bladder tumors and are associated with disease progression and reduced response to immunotherapies. The bladder cancer TME provides multiple signals that promote Treg recruitment, expansion, and functional stabilization, including chemokine-mediated trafficking, metabolic adaptation, and cytokine-driven differentiation. Interactions between Tregs and other microenvironmental components, such as cancer-associated fibroblasts, tumor-associated macrophages, endothelial cells, and extracellular matrix elements, further reinforce the immunosuppressive niche that facilitates tumor survival and therapy resistance. Recent advances in single-cell transcriptomics, spatial profiling, and multiomics analyses have revealed substantial heterogeneity among tumor-infiltrating Tregs, suggesting the existence of specialized subsets with distinct functional and metabolic properties in the bladder TME. These emerging insights highlight the importance of understanding Treg–TME crosstalk in shaping the immune landscape of bladder cancer. Targeting the mechanisms regulating Treg recruitment, stability, or suppressive function may represent a promising strategy to enhance the efficacy of immunotherapies including Bacillus Calmette–Guérin therapy. This review summarizes recent advances in Treg biology in bladder cancer and highlights potential therapeutic strategies to modulate Treg-mediated immunosuppression in the TME.
Yusuke Fukiage, Nodoka Okubo, M. Taga et al.· Frontiers in Molecular Biosc...· 0 citations
Tumor microenvironment (TME)-induced immunosuppression is a major driver of cancer treatment failure and resistance to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are not only pivotal suppressors of effector immune responses but also central organizers of tumor-supportive metabolic, stromal, and cellular crosstalk. This review systematically summarizes the origin and phenotypic characteristics of MDSCs and the mechanisms governing their recruitment, expansion, and activation within the TME. This review integrates current knowledge of MDSC biology through two complementary frameworks. One framework highlights the bidirectional interactions between MDSCs and immune, tumor, stromal, endothelial, and adipocyte compartments. The other classifies therapeutic approaches according to their mechanisms and translational relevance, including combinations with immunotherapy. We further evaluate clinical translation, including lessons from unsuccessful or inconclusive trials, biomarker gaps, and rational combination strategies. Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.
Lisichen Zhu, Hui Liu, Sihan Zhang et al.· Cancer Letters· 0 citations