Editorial: Community Series in The Immunosuppressive Tumor Microenvironment and Strategies to Revert its Immune Regulatory Milieu for Cancer Immunotherapy: Volume II

Mazdak Ganjalikhani Hakemi^1*Nair JAYAKUMAR²

• ¹Istanbul Medipol University, Istanbul, Türkiye
• ²National Cancer Institute Center for Cancer Research, Bethesda, United States

pro-angiogenic milieu that fosters tumor adaptation and immune escape (1)(2)(3). Understanding and modulating the TME remain critical for unleashing the full potential of immunotherapy ( 4 ) .Building on the foundation of Volume I, this second volume of the community series "The Immunosuppressive Tumor Microenvironment and Strategies to Revert its Immune Regulatory Milieu for Cancer Immunotherapy" brings together original research, case studies, reviews, and systematic analyses that collectively address the multifaceted barriers imposed by the TME. The eleven accepted articles span rare cancer case insights, prognostic biomarkers, stromal dynamics, metabolic regulation, immune cell heterogeneity, and therapeutic innovations. Together, these contributions highlight the urgent need for integrative strategies that combine biomarker discovery, mechanistic insights, and translational approaches to overcome immunosuppression in cancer. A key dimension of this research topic is the characterization of rare or poorly studied tumors, where limited therapeutic options underscore the value of immune-based approaches. T-cell transfer, immune checkpoint inhibitors, and personalized mRNA vaccines, providing valuable insights into future approaches and translational gaps that need to be addressed to improve outcomes in these rare sarcomas. Essential roles of stromal architecture and immune checkpoints in shaping clinical outcomes. Were Collectively, these studies underscore stromal indices and checkpoint co-expression as key determinants for guiding immunotherapy (8)(9)(10). An understanding of the immune subset diversity or heterogeneity within the TME is critical for precision therapy. Siyuan Jiang et al. profiled γδ T cells in AML, identifying subsets with distinct functions, such as the strong correlation between NKG2D+ TIGIT-Vδ1 cells and improved survival, supporting their potential as biomarkers and/or therapeutic candidates in adoptive transfer approaches (13,14).In their elegantly designed study, Xuelian Wang et al demonstrated how a heterogeneous immune landscape plays essential predictive roles in determining the outcome of targeted immune therapy in adenoid cystic carcinoma of the head and neck. Their studies demonstrated how a desired higher immune infiltration is often countered by increased dominance of suppressive macrophages, revealing the paradox of concurrent immune abundance and dysfunction. Together, these studies demonstrate the importance of dissecting immune heterogeneity towards designing contextspecific interventions (13)(14)(15). In many cancers like multiple myeloma, an aggressive and incurable hematological malignancy, immune evasion and its regulatory molecular determinants are essential to their progression.Lanting Liu et al. demonstrated how DNp73, an inhibitor of TP53, induced proliferation, drug resistance, and immune evasion, by targeting MYCN and upregulating MYC target genes PD-L1 and CD47, highlighting DNp73 as a biomarker for immunotherapy targeting PDL1/CD47 blockade in patients (16).Tatiana Akimova et al. introduced a novel approach using antisense oligonucleotides to selectively target FOXP3+ regulatory T cells. This strategy depleted intratumoral Tregs without affecting peripheral populations, enhancing effector T-cell activity and inducing significant tumor regression in preclinical models. These findings provide proof-of-concept for precise targeting of immunosuppressive cells in the TME (1,16). The diverse contributions in this second volume collectively underscore the complexity of the immunosuppressive TME and the multiplicity of strategies required to counteract it. Several recurring themes emerge:1. Stromal orchestration of immune suppression as a central barrier across multiple tumor types.2. Immunometabolic reprogramming, particularly lipid and lactate metabolism, as key drivers of immune dysfunction.3. Immune checkpoint combinations and functional subset profiling as critical tools for precision immunotherapy. Microenvironment provide valuable insights into the complex multifactorial barriers to cancer immunotherapy and provides innovative strategies for reprogramming the TME. By integrating stromal biology, metabolic regulation, immune subset heterogeneity, and novel therapeutic approaches, the contributions collectively advance our understanding of how to modulate immunosuppressive networks. Ongoing collaborative efforts will be vital to translating these insights into effective clinical strategies, ultimately leading to better outcomes for patients with diverse malignancies.