Immunotherapy in the Battle Against Bone Metastases: Mechanisms and Emerging Treatments

Abstract

Bone metastases are a prevalent complication in advanced cancers, particularly in breast, prostate, and lung cancers, and are associated with severe skeletal-related events (SREs), including fractures, spinal cord compression, and debilitating pain. Conventional bone-targeted treatments like bisphosphonates and RANKL inhibitors (denosumab) reduce osteoclast-mediated bone resorption but do not directly impact tumor progression within the bone. This review focuses on examining the growing potential of immunotherapy in targeting the unique challenges posed by bone metastases. Even though immune checkpoint inhibitors (ICIs) have significantly changed cancer treatment, their impact on bone metastases appears limited because of the bone microenvironment's immunosuppressive traits, which include high levels of transforming growth factor-beta (TGFβ) and the immune-suppressing cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review underscores the investigation of combined therapeutic approaches that might ease these difficulties, such as the synergy of immune checkpoint inhibitors with agents aimed at bones (denosumab, bisphosphonates), chemotherapy, and radiotherapy, as well as the combination of immune checkpoint inhibitors with different immunotherapeutic methods, including CAR T-cell therapy. This review provides a comprehensive analysis of preclinical studies and clinical trials that show the synergistic potential of these combination approaches, which aim to both enhance immune responses and mitigate bone destruction. By offering an in-depth exploration of how these strategies can be tailored to the bone microenvironment, this review underscores the need for personalized treatment approaches. The findings emphasize the urgent need for further research into overcoming immune evasion in bone metastases, with the goal of improving patient survival and quality of life.

Keywords: bone metastases; immune checkpoint inhibitors; immunotherapy; osteoimmunology; tumor microenvironment.

Figure 1

Interplay of Immune Responses and Bone Microenvironment in Cancer Metastasis. This figure illustrates the interactions between the immune system and bone microenvironment during cancer metastasis. Central to this process are the tumor cells, which express specific antigens recognized by CD8+ T cells via the TCR-MHCI complex. These interactions are modulated by immune checkpoints, specifically the PD-1/PD-L1 pathway, highlighting the suppressive role of T cell activity. Various immune cells, including APCs, CD4+ T cells, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), Th1, and Th17 cells, contribute to the dynamic immune landscape. Key cytokines such as TGFβ, IL-17, and IL-6, along with RANKL (secreted by cancer cells and osteoblasts), are pivotal in enhancing osteoclast (OC) activity promoting bone resorption. This figure underscores the dual role of the immune system in both supporting and combating bone metastasis, delineating targets for potential therapeutic interventions in oncology (Figure was created with BioRender.com).

Figure 2

Modulation of Bone Metastasis by Immune Checkpoint and Signaling Inhibitors. This figure depicts the intricate interplay between the immune system and bone remodeling mechanisms in the context of bone metastases. Key elements include the immune checkpoints (PD-1/PD-L1 axis) and T cell receptor (TCR-MHCI complex) interactions that play crucial roles in immune evasion by tumor cells. The figure also highlights the impact of therapeutic agents such as anti-PD-1 antibodies, TGFβ inhibitors, and bone-targeted agents like Denosumab on these pathways. These treatments not only target immune suppression but also interfere with the osteoclastogenic activity mediated by RANKL, pivotal in bone resorption. Additionally, the use of CTLA-4 inhibitors like Ipilimumab further illustrates the therapeutic strategies to enhance anti-tumor immunity. This representation serves as a comprehensive guide to understanding the dual role of the immune system in promoting and inhibiting bone metastasis (Figure was created with BioRender.com).