# Pleiotropic and multicellular roles of lymphotoxin beta receptor in solid tumor immunity and therapeutic targeting

## TL;DR

This paper explores how the lymphotoxin beta receptor (LTβR) can both promote and suppress tumors, and how targeting it could improve immunotherapy for hard-to-treat solid cancers.

## Contribution

The paper introduces the dual role of LTβR in tumor immunity and proposes targeted therapeutic strategies to modulate it for better immunotherapy outcomes.

## Key findings

- LTβR agonism can induce tertiary lymphoid structures and immune infiltration in preclinical cancer models.
- LTβR signaling can either support tumor growth or enhance anti-tumor immunity depending on the context.
- Targeted delivery of LTβR agonists may improve immunotherapy responses in solid tumors.

## Abstract

Immunotherapy has transformed the treatment landscape of several malignancies, yet solid tumors such as pancreatic ductal adenocarcinoma (PDAC), glioblastoma multiforme (GBM), and triple-negative breast cancer (TNBC) remain largely resistant due to poor immune infiltration, immunosuppressive tumor microenvironments (TMEs) and, the limited success of T cell–centric strategies. The lymphotoxin-beta receptor (LTβR), a member of the tumor necrosis factor (TNF) receptor superfamily, is broadly expressed on stromal, endothelial, and myeloid cells within the TME and signals through both canonical and non-canonical NF-κB pathways. Depending on context and activation mode, LTβR can drive either tumor progression or anti-tumor immunity. While persistent LTβR signaling supports immunosuppressive macrophage phenotypes and promotes tumor growth in hepatocellular carcinoma, preclinical models of colorectal and cervical cancer have demonstrated that LTβR activation induces tertiary lymphoid structures (TLSs), high endothelial venules (HEVs), and immune infiltration, thereby improving responsiveness to immune checkpoint blockade (ICB). This perspective examines in depth the functional duality of LTβR and its emerging therapeutic potential in solid tumors. LTβR agonism has been shown to promote TLS formation and immune activation, whereas antagonistic strategies such as ligand traps may suppress tumor-supportive LTβR signaling in immunosuppressive compartments. Strategically localized LTβR stimulation presents a promising avenue to induce targeted immune reprogramming within the TME. We further explore LTβR’s interactions with key immune subsets—myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and tumor-associated macrophages (TAMs)—and its synergy with ICB and CAR T cell therapies. Selective LTβR modulation may reprogram the TME, overcome immunotherapy resistance, and broaden durable responses in refractory solid tumors.

Therapeutic potential of LTβR agonism. (A) Systemic delivery of LTβR agonism-based therapeutics. Engagement of LTβR by systemically administered agonistic antibodies or recombinant LTα1β2 ligand activates LTβR signaling on various cells including stromal, endothelial, and myeloid cells, resulting in broad target distribution and less spatially controlled receptor activation within and beyond the tumor microenvironment (TME). (B) Tumor-restricted delivery of LTβR agonism-based therapeutics. In contrast, tumor-targeted strategies such as LIGHT-expressing mesenchymal stromal cells (MSCs), tumor cells, or engineered fusion proteins comprising an anti-epidermal growth factor receptor (EGFR) targeting domain fused to LIGHT enhance intra-tumoral bioavailability and preferentially activate LTβR signaling within the TME. (C) LTβR activation within the TME. LTβR agonism induces the expression of chemokines and cytokines including CXCL13, CCL19, and CCL21, as well as adhesion molecules (e.g., ICAM-1, VCAM-1), and promotes high endothelial venule (HEV) differentiation. These coordinated events support tertiary lymphoid structure (TLS) neogenesis, enhance antigen presentation, and facilitate local dendritic cell–T cell cross-talk, collectively promoting anti-tumor immunity. (i.t.: intratumoral; s.c.: subcutaneus; i.v.: intravenous).A diagram illustrating two modes of delivery and effects of immunotherapy in tumor microenvironments. Panel A shows systemic delivery using LTβR agonist antibodies or recombinant LTα₁β₂ ligand leading to diffuse target distribution. Panel B depicts tumor-restricted delivery using LIGHT-MSC or LIGHT-tumor cell injections, and a fusion protein for targeted distribution. Panel C explores the tumor microenvironment, detailing stromal, MSC, TAM, and tumor cells, with LTβR activation prompting TLS and HEV formation, and the release of adhesion molecules and chemokines. Key cells include dendritic, macrophage, T, and B cells.

Therapeutic potential of LTβR agonism. (A) Systemic delivery of LTβR agonism-based therapeutics. Engagement of LTβR by systemically administered agonistic antibodies or recombinant LTα1β2 ligand activates LTβR signaling on various cells including stromal, endothelial, and myeloid cells, resulting in broad target distribution and less spatially controlled receptor activation within and beyond the tumor microenvironment (TME). (B) Tumor-restricted delivery of LTβR agonism-based therapeutics. In contrast, tumor-targeted strategies such as LIGHT-expressing mesenchymal stromal cells (MSCs), tumor cells, or engineered fusion proteins comprising an anti-epidermal growth factor receptor (EGFR) targeting domain fused to LIGHT enhance intra-tumoral bioavailability and preferentially activate LTβR signaling within the TME. (C) LTβR activation within the TME. LTβR agonism induces the expression of chemokines and cytokines including CXCL13, CCL19, and CCL21, as well as adhesion molecules (e.g., ICAM-1, VCAM-1), and promotes high endothelial venule (HEV) differentiation. These coordinated events support tertiary lymphoid structure (TLS) neogenesis, enhance antigen presentation, and facilitate local dendritic cell–T cell cross-talk, collectively promoting anti-tumor immunity. (i.t.: intratumoral; s.c.: subcutaneus; i.v.: intravenous).