Over the last century, human longevity has increased due to various public health policies, ultimately resulting in higher accessibility and affordability of healthcare services and treatment options. As a result, people die less frequently from infectious diseases but instead develop slow-damage accumulation conditions, such as cancer and cerebrovascular diseases (Jones et al., 2012, Murray and Lopez, 2013). When it comes to malignancies, it is of utmost importance to recognize that chemotherapy for both solid and hematological cancers emerged only half a century ago. Its development was initially an unintended outcome of both world wars, spurred by the discovery of bone marrow aplasia caused by nitrogen mustard derivatives. Later, it evolved through drug discovery efforts led by the Cancer Chemotherapy National Service Center in the United States. Early clinical approaches targeted the proliferative nature of leukemias and solid tumors, aiming to block cell cycle progression while largely overlooking the role of the tumor microenvironment (about which little was understood) and the immunological risks posed by the treatment regimens themselves (DeVita & Chu, 2008). Only decades after the routine use of classic chemotherapeutic agents did researchers begin to investigate their off-target immunological effects and post-treatment immune reconstitution. It is now known that nitrogen mustard derivatives, for example, can cause significant lymphodepletion, including prolonged reductions in CD4+ T cell counts, which may persist for years after treatment (García Muñoz et al., 2014). Chelating agents, such as cyclophosphamide, have dose-dependent effects: higher doses lead to lymphodepletion (Hirayama et al., 2019), while lower doses exhibit immunomodulatory effects, boosting anti-tumor T-cell responses and reducing regulatory T cell numbers in tumors (Hughes et al., 2018). A systematic approach to the immune regulatory off-target effects and immunogenic potential of classic chemotherapy was only undertaken in the early 2000s, alongside efforts to develop novel immunotherapeutic approaches. Translational models, for instance, supported the idea that, unlike other agents, anthracyclines - widely used in the treatment of leukemias, lymphomas, and solid tumors such as breast cancer - despite being a classic drug, exhibit immunogenic potential (Casares et al., 2005). The immunogenic cell death of neoplastic tissues highly depends on immunological fitness. And this concept leads to another question, which is the role of cellular immunosenescence in anti-tumoral responses. Although older individuals, typically express high levels of circulating CD4+ T cells and tissue-resident memory CD4+ T cells, they display lower levels of naïve CD4+ T cells and are more susceptible to infections and diseases such as cancer (Farber, Yudanin, & Restifo, 2014). The concept of immunosenescence—a double-edged sword impacting both the development and treatment of hematological malignancies—plays a fundamental role in these diseases, which have increased in incidence over the last decades, particularly among elderly patients (Zhang et al., 2023). Considering an aged population with hematolymphoid malignancies, one must take into account several factors that may restrict the effectiveness of immunotherapeutic approaches. Firstly, patients pretreated with classical chemotherapeutic agents, depending on the regimens they were exposed to, may have undergone a defective immune reconstitution, which may hinder anti-tumor immune effector functions in the event of disease recurrence. Secondly, aged patients tend to have a lower immunological fitness. If patients are to be treated with novel immunotherapeutic approaches, coadjuvant strategies may be desirable to rescue and boost immune effector functions.

In this review, we discuss the role of different immunostimulatory cytokines that have undergone clinical trial testing in the setting of hematological malignancies. Concerning the age group typically affected by these pathologies, the significant impact of age-associated immunosenescence, and the hematolymphoid involvement by the disease itself, we explore the potential synergistic effects of combining cytokines with new immunomodulatory agents or adoptive cellular therapies, such as hematopoietic stem cell transplantation and chimeric antigen receptor (CAR) T-cell therapy.