Chemotherapy has been the basis of advanced cancer treatment for decades. This therapy has largely been considered immunosuppressive, yet accumulated preclinical and clinical evidence shows that certain chemotherapeutic drugs, under defined conditions, may stimulate antitumor immunity and potentiate immune checkpoint inhibitor (ICI)-based therapy. Its effectiveness has been highlighted by recent regulatory approvals of various combinations of chemotherapy with ICIs in several tumors, particularly in some difficult-to-treat cancers. This review discusses the immune modulatory properties of chemotherapy and how they may be harnessed to develop novel chemo-immunotherapy combinations. It also highlights the key determinants of the success of chemo-immunotherapy and provides an overview of the combined chemo-immunotherapies that have been clinically approved.

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

Treatment based on immune checkpoint blockade has revolutionized cancer therapy. Despite the remarkable success achieved and the preclinical development of multiple checkpoint inhibitors targeting other checkpoints, only antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have been approved for patient treatment, especially in solid tumors. Currently, with the approval of relatlimab, a LAG-3 blocking antibody, a third player, has been used in the fight against cancer. The endorsement of relatlimab marks a significant milestone in cancer immunotherapy, opening new avenues for combination therapies and enhancing treatment outcomes. However, the complex biology of LAG-3 may hinder its full development as a therapeutic alternative. In this review, we provide in-depth insight into the biology of LAG-3 and its current and future development in cancer treatment.

Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal malignant B cells and heterogeneous clinical outcomes. This study explored the role of the immune checkpoint receptor LILRB4 (ILT3), previously implicated in acute myeloid leukemia, in the pathogenesis and progression of CLL. Analysis of 126 CLL patient samples revealed aberrantly elevated LILRB4 expression on leukemic B cells, with higher levels observed in advanced disease stages. Elevated LILRB4 expression was correlated with shorter time-to-treatment intervals and reduced overall survival, highlighting its potential as a prognostic marker. Mechanistically, LILRB4 was enriched in a proliferative leukemic subpopulation driven by the TLR9 and BTK signaling pathways. Functional assays demonstrated that LILRB4 promotes immune evasion by suppressing T and NK cell-mediated cytotoxicity, while its blockade restored immune effector activity and impaired leukemic cell migration. Furthermore, elevated levels of soluble LILRB4 (sLILRB4) in patient serum are associated with poor clinical outcomes, including an increased incidence of secondary malignancies. Receiver operating characteristic (ROC) analysis demonstrated the high sensitivity and specificity of sLILRB4 as a biomarker for disease progression. Collectively, these findings identify membrane-bound LILRB4 as a mediator of immune suppression and disease progression in CLL, while highlighting sLILRB4 as a potential biomarker associated with poor clinical outcomes. Further investigations into LILRB4-directed therapies could pave the way for improved patient stratification and novel treatment strategies in CLL patients.

Glioblastoma stands as the most frequent primary brain tumor. Despite the multimodal therapy for glioblastoma patients, the survival rate is very low, highlighting the need for novel therapies that improve patient outcomes. Immune checkpoint blockade strategies are achieving promising results in a myriad of tumors and several studies have reported its efficacy in glioblastoma at a preclinical level. ILT2 is a novel immune checkpoint that exerts an inhibitory effect via the interaction with classical and non‐classical HLA class‐I molecules. Herein, we report that ILT2 blockade promotes antitumor responses against glioblastoma. In silico and immunohistochemical analyses revealed that the expression of ILT2 and its ligands HLA‐A, ‐B, ‐C, and ‐E are highly expressed in patients with glioblastoma. Disruption of ILT2 with blocking monoclonal antibodies increased natural killer cell‐mediated IFN‐γ production and cytotoxicity against glioblastoma, partially reverting the immunosuppression linked to this malignancy. In addition, co‐treatment with temozolomide strengthened the antitumor capacity of anti‐ILT2‐treated immune cells. Collectively, our results establish the basis for future studies regarding the clinical potential of ILT2 blockade alone or in combination regimens in glioblastoma.