Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors — cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) — and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Spinal cord gliomas are rare entities that often have limited surgical options. Immunotherapy has shown promise in intracranial gliomas with some research suggesting benefit for spinal cord gliomas. A focused review of immunotherapies that have been investigated in spinal cord gliomas was performed. The primary methods of immunotherapy investigated in spinal cord gliomas include immune checkpoint inhibitors, adoptive T-cell therapies, and vaccine strategies. There are innumerable challenges that must be overcome to effectively apply immunotherapeutic strategies to the spinal cord gliomas including low incidence, few antigenic targets, the blood spinal cord barrier, the immunosuppressive tumor microenvironment and neurotoxic treatment effects. Nonetheless, research has suggested ways to overcome these challenges and treatments have been effective in case reports for metastatic non-small cell lung cancer, melanoma, midline glioma and glioblastoma. Current therapies for spinal cord gliomas are markedly limited. Further research is needed to determine if the success of immunotherapy for intracranial gliomas can be effectively applied to these unique tumors.

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and dampen the immune response, negatively affecting patient survival. Therefore, targeting TAMs could address the limitations of current cancer treatments. However, drug development in this area remains limited. The leukocyte-associated Ig-like receptor 1 (LAIR1), also called CD305, is prominently expressed on the surface of TAMs. We have uncovered what we believe to be a previously unrecognized immunosuppressive LAIR1/factor XIII A/collagen IV pathway across various cancer types. Inhibition of LAIR1, either through knockout ( Lair1 ^–/– ), antibody blockade (anti-Lair1 antibody), or a chimeric antigen receptor (CAR) design (3-in-1 CAR by combining tumor targeting, T cell trafficking, and remodeling of the immunosuppressive TME in 1 CAR construct) provided an enhanced antitumor response. LAIR1 inhibition enhanced peripheral and intratumoral CD8 memory T cell populations, induced a phenotypic shift of M2-like macrophages toward M1 macrophages, and normalized tumor collagen IV and structural components in the TME, facilitating effective tumor–T cell interactions and tumor suppression. Enhanced antitumor responses were observed when Lair1 ^–/– or anti-Lair1 antibody was used alone or in combination with CAR T cells or when the 3-in-1 CAR T cells were used solely in tumor models resistant to chemotherapy–radiation–programmed cell death protein 1 (PD-1) blockade. These findings position LAIR1 inhibition as a promising strategy for cancer immunotherapies.