Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has the highest proportion of homologous recombination deficiency (HRD). HRD has been considered a biomarker of response to immune checkpoint inhibitors (ICIs), but the reality is more complicated. A comprehensive comparison of the tumor microenvironment (TME) in HRD and non-HRD TNBC samples may be helpful. Datasets from single-cell, spatial, and bulk RNA-sequencing were collected to explore the role of HRD in the development of TME at multiple scales. Based on the findings in the TME, machine learning algorithms were used to construct a response prediction model in eleven ICI therapy cohorts. A more exhausted phenotype of T cells and a more tolerogenic phenotype of dendritic cells were found in the non-HRD group. HRD reprograms the predominant phenotype of cancer-associated fibroblasts (CAFs) from myofibroblastic CAFs to inflammatory-like CAFs. As interactions between myofibroblastic CAFs and other cells, DPP4-chemokines associated with reduced immune cell recruitment were unique in the non-HRD group. The prediction model based on DPP4-related genes had acceptable performance in predicting response, prognosis, and immune cell content. Higher HRD scores in bulk RNA-sequencing samples indicated more activated immune cell function, but not higher immune cell content, which may be affected by factors such as antigen-presenting capacity. Based on multi-scale transcriptomics, our findings comprehensively reveal differences in the TME between HRD and non-HRD samples. Combining HRD with the prediction model or other methods for assessing immune cell content, may better predict response to ICIs in TNBC.

Brain metastasis (BM) occurs commonly in patients with lung adenocarcinomas. Limited evidence indicates safety and efficacy of immunotherapy for this metastatic tumor, though immune checkpoint blockade has become the front-line treatment for primary advanced non-small cell lung cancer. We aim to comprehensively compare tumor microenvironments (TME) between primary tumors (PT) and BM at single-cell resolution. Single-cell RNA transcriptomics from tumor samples of PT (N = 23) and BM (N = 16) and bulk sequencing data were analyzed to explore potential differences in immunotherapeutic efficacy between PT and BM of lung adenocarcinomas. Multiple machine learning algorithms were used to develop and validate models that predict responses to immunotherapy using the external cohorts. We found obviously less infiltration of immune cells in BM than PT, characterized specifically by deletion of anti-cancer CD8+ Trm cells and more dysfunctional CD8+ Tem cells in BM tumors. Meanwhile, macrophages and dendritic cells within BM demonstrated more pro-tumoral and anti-inflammatory effects, represented by distinct distribution and function of SPP1+ and C1Qs+ tumor-associated microphages, and inhibited antigen presentation capacity and HLA-I gene expression, respectively. Besides, we also found the lack of inflammatory-like CAFs and enrichment of pericytes within BM tumors, which may be critical factors in shaping inhibitory TME. Cell communication analysis further revealed mechanisms of the immunosuppressive effects associated with the activation of some unfavorable pathways, such as TGFβ signaling, highlighting the important roles of stromal cells in the anti-inflammatory microenvironment, especially specific pericytes. Furthermore, pericyte-related genes were identified to optimally predict immunotherapeutic responses by machine learning models with great predictive performance. Overall, various factors contribute to the immunosuppressive TME within BM tumors, represented by the lack of critical anti-cancer immune cells. Meanwhile, pericytes may help shape the TME and targeting the associated mechanisms may enhance immunotherapy efficacy for BM tumors in patients with lung adenocarcinomas.

Hematologic malignancies are frequently complicated by malnutrition, a condition that remains underrecognized yet strongly associated with impaired treatment tolerance, immune recovery, and survival. Unlike solid tumors, hematologic malignancies are characterized by diffuse marrow and immune system involvement, rendering host metabolism highly vulnerable to tumor-driven inflammation and therapy-induced immune stress. Accumulating evidence indicates that nutritional deterioration in hematologic malignancies reflects a state of integrated immunometabolic vulnerability—driven by hyperinflammation, anabolic resistance, gastrointestinal injury, and psychosocial stress—rather than inadequate caloric intake alone. This review synthesizes current evidence on the biological basis, clinical assessment, and management of malnutrition in hematologic malignancies, with particular emphasis on hematopoietic stem cell transplantation and cellular therapies. We propose that nutritional care in hematologic malignancies should evolve from supportive supplementation toward mechanism-informed, precision nutritional strategies aimed at modulating host metabolism and immune function to improve clinical outcomes.

Pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are distinct from adult forms and occur less frequently. We identified 7,871 children and 226,211 adults with lymphoma from the Surveillance, Epidemiology, and End Results database from 1975 to 2018. The age-adjusted incidence rate for pediatric lymphoma was 24.5 per million persons (95% CI: 24.0-25.1), comprising 13.0 per million (95% CI: 12.6–13.4) for HL and 11.5 per million (95% CI: 11.1–11.9) for NHL. In comparison to adult lymphoma, pediatric lymphoma showed no significant changes in incidence from 1975 to 2002 (annual percentage change, APC = -0.12 ± 0.19, P = 0.53), but displayed an observable increase after 2003 (APC = + 1.31 ± 0.45, P = 0.006). Among pediatric cases, the 5-year limited-duration prevalence rate increased from 0.00691% in 1996 to > 0.009% in recent years, and the 20-year rate rose from 0.0109% in 1996 to 0.0148% in 2018. In alignment with the observed decrease in incidence over the recent decade, the prevalence of adult lymphoma exhibited a more gradual growth post-2007. Among adult patients, the age-adjusted mortality rate demonstrated an initial increase in the periods 1975–1977 (APC = + 41.06 ± 6.23, P < 0.001), 1977–1980 (APC = + 9.83 ± 4.27, P = 0.036), 1980–1989 (APC = + 5.24 ± 0.36, P < 0.001), and 1989–1994 (APC = + 2.27 ± 0.86, P = 0.014), followed by a subsequent decrease after 1994 (APC= -0.49 ± 0.05, P < 0.001). In contrast, the mortality rates of pediatric lymphoma exhibited a consistent decrease over the past four decades (1975–2018: APC= -3.12 ± 0.29, P < 0.001), resulting in an overall age-adjusted mortality rate of 2.92 (95% CI: 2.73–3.11).