Deciphering immune cell crosstalk and dysregulation in cancer for effective immunotherapeutic strategies

The field of cancer immunology and immunotherapy is witnessing rapid advances as researchers strive to overcome persistent challenges related to immune resistance and tumor immune evasion. Despite significant breakthroughs, such as the clinical success of immune checkpoint inhibitors and CAR-T cell therapies, many patients exhibit only partial or transient responses. The tumor microenvironment (TME) plays a central role in shaping these outcomes by orchestrating intricate interactions among immune cells, stromal components, and malignant cells. Recent studies have highlighted the dichotomous functions of T cells and tumor-associated macrophages (TAMs), where a loss of T cell function through exhaustion or suppression and the pro-tumoral reprogramming of TAMs are major obstacles to sustained antitumor immunity. This dynamic interplay is further complicated by the emergence of metabolic competition, immune checkpoint regulation, and the influence of neoantigens, all of which regulate immune cell infiltration, transition, and dysfunction in the TME.

Ongoing research reveals that reversing T cell exhaustion, reprogramming immunosuppressive macrophages, and deciphering the molecular cues guiding immune cell trafficking could significantly improve immunotherapy outcomes. Seminal findings underscore the relevance of cell-to-cell communication via cytokines, chemokines, and metabolic competition, which collectively dictate the fate and function of immune cell populations in tumors. However, current knowledge is limited by an incomplete understanding of how spatial organization, molecular signaling, and the presence of tumor neoantigens interact to either support or hinder effective anticancer immunity. Novel combinatorial therapies and predictive biomarkers are urgently needed to bridge basic discoveries with clinical application and to address resistance mechanisms in diverse cancer contexts.

This Research Topic aims to unravel the molecular, cellular, and spatial mechanisms underpinning immune cell crosstalk, infiltration, transition, and dysfunction in the TME, with an emphasis on identifying actionable targets and biomarkers that can enhance immunotherapy efficacy. The overarching goal is to dissect how communication pathways between immune cells and between immune and stromal cells govern functional plasticity, immune surveillance, and therapeutic resistance. Particular attention will be paid to the factors mediating T cell exhaustion, TAM polarization, neoantigen-driven immune recognition, and their implications for the design of personalized immunotherapeutic regimens. This focus seeks to foster the translation of mechanistic insights into novel strategies that improve the prognosis and quality of life of cancer patients.

The scope of this Research Topic is centered on mechanistic studies and translational research addressing immune cell behavior and interactions within the tumor microenvironment, including both human and preclinical models. Studies outside of the cancer context or without a mechanistic emphasis are beyond the primary scope. To gather further insights in cancer immune cell networks and immunotherapeutic development, we welcome articles addressing, but not limited to, the following themes:

• Immune cell differentiation or migration (including T cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and natural killer cells) in cancer
• Immune cell metabolism and its impact on antitumor function
• Cellular landscape and crosstalk analyses, including identification of critical immune subsets and molecular biomarkers within the TME
• Role of neoantigens in shaping cancer immunity and development of targeted immunotherapies
• Signal transduction pathways governing immune cell behavior in malignancy
• Emerging immunotherapeutic strategies, including dendritic cell vaccines, immune checkpoint inhibitors, antibody-drug conjugates, and CAR-based therapies
• Innovative approaches at the interface of medical and engineering disciplines for advancing immunotherapy

We invite submissions of original research articles, reviews, perspectives, and brief reports relevant to the aforementioned areas.