Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) representing the majority of diagnosed cases. NSCLC encompasses several histological subtypes, prominently adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Among these, lung adenocarcinoma (LUAD) has emerged as the most prevalent and fatal, exhibiting a worrying trend of increasing incidence years over years. Despite advances in treatment modalities, including surgery, chemotherapy, and targeted therapies, the prognosis for LUAD patients remains grim. However, the advent of immune checkpoint inhibitors (ICIs), particularly targeting the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) axis, has revolutionized the therapeutic landscape. Yet, the response rates to PD-1/PD-L1 blockade remain suboptimal, illuminating an urgent need to unravel additional components of the tumor-immune microenvironment that may influence immunotherapy sensitivity.
The tumor microenvironment in LUAD is often characterized by a ‘cold tumor’ immunophenotype, where CD8+ cytotoxic T lymphocytes, the primary effectors mediating anti-tumor immunity, are conspicuously scarce. This scarcity correlates with reduced PD-1 expression on T cells, diminishing the efficacy of PD-1/PD-L1 ICIs, which fundamentally rely on the reactivation of these exhausted T cells. The immunological coldness of LUAD suggests that focusing exclusively on T cell-centered therapies might be insufficient. Consequently, the scientific community has turned its attention to other immune cell populations within the tumor milieu to identify alternative pathways and targets that might bolster anti-tumor immunity or overcome resistance mechanisms to current ICIs.
Among the various immune cell subsets, B lymphocytes have historically been underexplored in the field of tumor immunology. Traditionally recognized for their roles in humoral immunity through antibody production and antigen presentation, B cells were initially considered peripheral to cancer immunosurveillance. However, emerging evidence suggests that B cells are not merely bystanders but active participants modulating the tumor immune landscape. Intriguingly, recent investigations highlight that B cell infiltration into tumors correlates with improved prognosis and enhanced response to immunotherapy across multiple solid cancers, including melanoma, breast cancer, and more recently, lung cancer.
In lung adenocarcinoma, B cells display higher levels of infiltration and activation compared to squamous cell carcinoma, indicating distinctive immune dynamics within the LUAD microenvironment. The functional heterogeneity of tumor-infiltrating B cells is vast, encompassing subpopulations such as regulatory B cells (Bregs), memory B cells, and plasma cells, each exhibiting unique roles that can be either pro-tumorigenic or anti-tumorigenic depending on context. Understanding this dualistic nature is pivotal, as it may allow for the manipulation of B cell subsets to favor anti-tumor immunity and improve therapeutic outcomes.
Mechanistically, B cells contribute to anti-tumor immunity via several pathways beyond antibody production. These cells serve as potent antigen-presenting cells (APCs), capable of activating CD4+ and CD8+ T cells by processing and presenting tumor-associated antigens in the context of MHC molecules. Furthermore, B cells secrete an array of cytokines, such as interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), that shape the immune milieu, either supporting immune activation or suppression. The balance of these signals may dictate the extent of immune infiltration and tumor control.
Importantly, the spatial organization of B cells within tertiary lymphoid structures (TLS) in the tumor microenvironment has emerged as a critical factor influencing immunotherapy responsiveness. Presence of TLS, ectopic lymphoid aggregates resembling secondary lymphoid organs, is associated with T cell priming and more robust anti-tumor immunity. In LUAD, high densities of B cell-rich TLS correlate with favorable survival outcomes and heightened responsiveness to ICIs. These findings posit that augmenting TLS formation or function might represent a novel immunotherapeutic strategy.
From a translational standpoint, profiling B cell signatures in LUAD could serve as predictive biomarkers, identifying patients more likely to benefit from ICI therapies or combination treatments. Several gene expression studies have identified B cell-associated transcripts correlated with improved prognosis and treatment response. This contrasts with the signature profiles in lung squamous cell carcinoma, where B cell involvement is comparatively less pronounced, further underscoring the unique immunobiology of LUAD.
The therapeutic implications of these insights are profound. Currently, PD-1/PD-L1 therapies primarily target T cell exhaustion pathways, but integrating strategies that harness B cell immunity could synergistically overcome resistance. Potential interventions include B cell-activating vaccines, monoclonal antibodies targeting B cell inhibitory receptors, or agents promoting TLS development within tumors. Additionally, disrupting immunosuppressive Breg populations may release constraints on effective anti-tumor immune responses.
Beyond influencing adaptive immunity, B cells may also impact the tumor microenvironment through interactions with stromal cells, dendritic cells, and macrophages, modulating processes such as angiogenesis, extracellular matrix remodeling, and immune cell trafficking. This multifaceted role demands comprehensive characterization using single-cell sequencing, multiplex imaging, and functional assays to delineate B cell heterogeneity and intercellular crosstalk.
The dynamic interplay between B cells and other immune components in LUAD may also shape resistance pathways. For instance, aberrant B cell signaling could contribute to immune evasion by fostering an immunosuppressive niche or inducing regulatory T cell recruitment. Targeting these mechanisms could reinvigorate immune surveillance and facilitate durable clinical responses.
Intriguingly, pediatric and adult cancers differ in their B cell responses, with age-related changes in immune composition impacting therapy outcomes. In LUAD, which predominantly affects older adults, understanding the immunosenescence of B cells could inform personalized immunotherapy regimens tailored to enhance B cell function.
Despite the promise of targeting B cells, challenges remain. B cell depletion therapies, such as anti-CD20 monoclonal antibodies used in hematological malignancies, might adversely affect anti-tumor immunity in solid tumors if applied indiscriminately. Therefore, precision approaches that selectively modulate beneficial B cell subsets while sparing or suppressing pro-tumorigenic populations are imperative.
Continued investigation into the molecular signaling pathways governing B cell activation, differentiation, and interaction with tumor cells in LUAD will enable the design of next-generation immunotherapies. Key pathways under scrutiny include the B cell receptor (BCR) signaling cascade, co-stimulatory molecules like CD40-CD40L, and cytokine-mediated crosstalk influencing immune homeostasis.
In conclusion, the evolving recognition of B cells as crucial mediators within the LUAD tumor microenvironment heralds a paradigm shift in cancer immunology. By expanding the focus beyond T cells, researchers aim to unlock novel therapeutic avenues that could substantially improve outcomes for patients suffering from this lethal disease. Interdisciplinary collaboration integrating immunology, oncology, and computational biology will be instrumental in translating these findings from bench to bedside, ushering in a new era of precision immunotherapy for lung adenocarcinoma.
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Subject of Research: Role of B cell immunity in lung adenocarcinoma and its impact on tumor microenvironment and immunotherapy outcomes
Article Title: The role of B cell immunity in lung adenocarcinoma
Article References: Shu, L., Tao, T., Xiao, D. et al. The role of B cell immunity in lung adenocarcinoma. Genes Immun (2025). https://doi.org/10.1038/s41435-025-00331-9
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41435-025-00331-9
