Editorial: Formation of Immunological Niches in Tumor Microenviro nments: Mechanisms and Therapeutic Potential

Xiaosheng Tan^1*Zilu Chen²Qingyu Luo^3*Weiling Li^4*Ying Luo⁵

• ¹Rutgers, The State University of New Jersey, New Brunswick, United States
• ²Rutgers Cancer Institute, New Brunswick, United States
• ³One Patient One Cure, Boston, United States
• ⁴Dalian Medical University, Dalian, China
• ⁵The University of Texas Southwestern Medical Center, Dallas, United States

Introduction Immunological niches in tumor microenvironments (TME) are spatially organized funct ional units where tumor cells interact with immune and stromal components through dynamic molecular networks[1]. These specialized microdomains exhibit dual functionality: while capa ble of supporting anti-tumor immunity through immune cell activation, they frequently evolve immunosuppressive properties that enable immune evasion and therapy resistance[2]. Emergi ng evidence reveals that niche characteristics significantly influence immunotherapy response s, with distinct spatial architectures associated with treatment sensitivity or resistance across c ancer types[3]. Understanding these regulatory mechanisms provides critical insights for deve loping strategies to reprogram immunosuppressive niches therapeutically. Decoding Niche Formation: Cellular and Molecular Architects Immunological niches within tumors emerge through coordinated interactions between t hree fundamental components: (1) tumor cells displaying antigenic and metabolic heterogenei ty, (2) immune populations (CD8+ T cells, tumor-associated macrophages [TAMs], dendritic c ells [DCs]), and (3) stromal elements (cancer-associated fibroblasts [CAFs], extracellular matr ix [ECM], vasculature). These components communicate through cytokine-chemokine networ ks (e.g., IFN-γ-mediated immune activation versus TGF-β-driven suppression) and direct cell-contact signals (e.g., PD-1/PD-L1 checkpoint interactions) to collectively regulate anti-tumor i mmunity[2; 4]. At the cellular level, stromal components - particularly CAFs - have been identified as k ey architectural regulators[5]. Single-cell multi-omics approaches have enabled precise charac terization of CAF heterogeneity. For instance, in colon adenocarcinoma, an 11-gene CAF sign ature effectively stratified patients into high-and low-risk groups, with the high-risk group ex hibiting greater immune infiltration yet paradoxically lower drug sensitivity [6]. Similarly, in t riple-negative breast cancer (TNBC), Ding et al.[7] established a prognostic model where high -risk patients showed increased stromal CAF and endothelial cells infiltration and poorer clini cal outcomes. At the molecular level, pathway activation analyses reveal critical mediators of niche fu nctionality[8]. A pan-cancer study demonstrated that EGFR pathway activation drives immuno therapy resistance through an EGFR-related gene signature (EGFR.Sig), which correlates with elevated exhaustion markers (TIM-3, LAG-3) and immunosuppressive ligands (PD-L1, CD4 7) [9]. The convergence of these molecular and cellular pathways underscores the need for mu ltidimensional therapeutic approaches targeting niche formation at multiple levels, a direction that may overcome therapeutic resistance and improve clinical outcomes. Biomarkers: From Niches to Clinical Tools Beyond mechanistic insights, translating immunological niches into clinically actionabl e biomarkers has become a critical frontier in precision oncology[10]. Systemic inflammation indices derived from peripheral blood have demonstrated clinical utility as non-invasive niche proxies. As demonstrated in our Research Topic, these indices provide valuable insights for cl inical prognosis and treatment strategies: In esophageal cancer, the systemic immune-inflamm ation index (SII) was identified as an independent prognostic factor for recurrence-free surviv al after esophagectomy [11]. In breast cancer, elevated preoperative systemic inflammation res ponse index (SIRI) served as an independent risk factor for disease-free survival [12]. Similarl y, in locally advanced cervical cancer, the pan-immune-inflammation value (PIV) was establis hed as a robust and independent prognostic factor significantly correlated with overall surviva l and disease-free survival [13]. Niche-informed molecular subtyping is transforming patient stratification: In acute mye loid leukemia, molecular subtyping based on ligand-receptor (LR) pairs has unveiled distinct i mmune landscapes and prognostic differences. A scoring model termed LR.score effectively st ratifies patients by survival risk and reflects the degree of T-cell dysfunction, offering insights into niche-driven immune dysregulation and therapy resistance [14]. In melanoma, aryl hydro carbon receptor (AhR)-related gene signatures (MAP2K1, PRKACB, KLF5, and PIK3R2) hav e been identified as a potential prognostic tool, strongly associated with immune infiltration an d tumor progression, providing a robust prognostic framework and potential therapeutic target s [15]. These advances collectively represent a paradigm shift in cancer management, where ni che-derived biomarkers are moving from research tools to clinical implementation. By capturi ng the complex interplay between tumor cells and their microenvironment, these biomarkers e nable more precise patient stratification and treatment selection[16]. Therapeutic Strategies: Rewriting Niche Rules Although biomarkers yield valuable insights into niche dynamics, converting these findi ngs into effective treatments remains a major challenge. To bridge this gap, therapeutic develo pment is increasingly directed at reprogramming the tumor–immune interface by modulating n iche biology through diverse approaches[17]. Targeting immune-related molecules remains a well-established and effective therapeuti c approach. For example, RAC3 has been shown to drive tumor aggressiveness and immune e vasion in bladder cancer, positioning it as a potential dual biomarker and therapeutic target[18]. Stromal remodeling strategies are also gaining prominence. Clinical translation is alread y evidenced by the success of anlotinib (an anti-angiogenic agent) combined with anti-PD-L1 therapy in high-grade serous ovarian cancer. This combination therapy inhibits angiogenesis, e nhances immune infiltration while simultaneously reinvigorating exhausted T cells [19], demo nstrating the therapeutic potential of coordinated niche modulation. Tumor metabolic regulators coordinate immune–tumor cell networks within the TME, a nd targeting these metabolic vulnerabilities represents a promising yet clinically challenging t herapeutic avenue[20]. Ferroptosis inducers such as erastin enhance immunogenic cell death b y releasing damage-associated molecular patterns (DAMPs) that recruit and activate immune c ells, while lipid peroxides generated during ferroptosis may potentiate immune cell–mediated tumor killing [21]. In parallel, repurposing existing drugs such as metformin modulates the im mune microenvironment, enhances the efficacy of immunotherapy and radiotherapy, and over comes resistance in "cold" or refractory tumors, all while maintaining a favorable safety profil e[22]. Notably, microbiome-targeted strategies are opening new therapeutic dimensions[23]. T LR3 agonists, including Poly(I: C), have been shown to restore immune competence in colore ctal cancer models with viral dysbiosis [24], offering novel combination approaches. Collectively, these diverse strategies demonstrate how targeting niche biology across str omal, metabolic, epigenetic, and microbial axes can help dismantle long-standing therapeutic barriers and expand the efficacy of cancer immunotherapy. Clinical Challenges and Future Directions Despite remarkable progress, significant challenges remain in translating niche biology into clinical practice[3]. The dynamic nature of immunological niches complicates therapeutic targeting, as exemplified by cellular senescence transitioning from tumor-suppressive (p53/p2 1/p16-mediated) to pro-tumorigenic SASP states during cancer progression [25]. This plasticit y necessitates precisely timed interventions and robust biomarkers to identify optimal treatme nt windows. Unexpected systemic effects further complicate therapeutic development, with immune checkpoint inhibitors causing immune-related adverse events like myositis in up to 30% of pat ients [26]. Emerging monitoring tools, including impedance myography and advanced serum biomarkers [27], offer potential mitigation through early detection. Technological innovations will be crucial for addressing niche complexity. Multiplex im munohistochemistry, spatial transcriptomics, and AI-enhanced image analysis are enabling hig h-resolution maps of niche organization and evolution. These tools are particularly valuable in elucidating resistance mechanisms and tailoring personalized therapeutic strategies[28; 29]. I ntegrating these technologies into clinical trials will be vital for translating niche biology into individualized cancer care. Conclusion The formation and regulation of immunological niches within the TME represent both c hallenges and opportunities in cancer therapy. As evidenced throughout this Research Topic, ta rgeting niche components—including immune, stromal, metabolic, and microbial elements—c an enhance therapeutic precision and improve patient outcomes. Looking forward, a deeper m echanistic understanding and integrative translational efforts are indispensable to transform ni che biology from conceptual frameworks into clinically actionable strategies for precision onc ology.