Unraveling the immune microenvironment in primary CNS lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare malignant lymphoid condition that arises within the central nervous system, which is considered an immune-privileged site. Outcomes for patients with PCNSL have substantially improved over the past decade, largely due to treatment intensification. In recent years, it has become increasingly evident that the biology of PCNSL is not solely determined by the tumor itself, but also by its close and complex interaction with the immune microenvironment. Tumor-infiltrating lymphocytes, tumor-associated macrophages, and dendritic cells, in particular, reshape the immune milieu in PCNSL. Notably, an immunosuppressive microenvironment characterized by a high concentration of M2-like macrophages, a low concentration of CD8+ T-cells, and high expression of the cytokine IL-10 is associated with an unfavorable survival. Conversely, T-cell immunity and its abundance are pivotal for favorable treatment outcomes, highlighting the prognostic importance of immune competence within the central nervous system. The current standard of care for induction treatment is based on high-dose methotrexate as the central component, followed by consolidating high-dose chemotherapy and autologous stem cell transplantation in eligible patients. Long-term follow-up data from the IELSG32 and PRECISE trials demonstrated that up to 70% of patients remained alive at seven years, underscoring the curative potential of these strategies. Eligibility mainly depends on performance status, which is recognized as a key prognostic factor in standard risk stratifications. Nevertheless, relapse rates remain substantial, prompting growing interest in immunotherapeutic strategies. T-cell-based approaches, including among others checkpoint inhibitors, T-cell engagers, and CAR T-cells have achieved encouraging therapeutic success. However, the immune-privileged nature of the central nervous system poses immunological challenges that limit immune surveillance and facilitate tumor cell evasion, creating therapeutic obstacles in PCNSL. A comprehensive understanding of the manner in which alterations in oncogenic signaling influence immune evasion strategies holds considerable potential for enhancing future therapeutic approaches in PCNSL. Despite compelling evidence that the immune microenvironment significantly influences disease progression, established prognostic models for PCNSL do not yet consider inflammatory or immunological biomarkers. Given the significant prognostic and therapeutic implications of the immune microenvironment, its impact should be reflected and validated in future standard risk stratifications. Integrating validated immune biomarkers with emerging immunotherapeutic strategies has the potential not only to improve individual patient outcomes but also to optimize the overall structure of care for patients with PCNSL.