Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7 ⁺ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non–small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)–driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1–major histocompatibility complex class 1 (MHC-I) and –MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (T _FH ) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

Breast cancers with a stiff extracellular matrix (ECM) frequently evade immune surveillance through mechanisms that remain incompletely understood. Here, we identify a mechanosensitive immune-evasion pathway governed by the phosphorylation-dependent prolyl isomerase Pin1. We show that ECM rigidity stabilizes Pin1 and promotes its nuclear accumulation in cancer cells, where it preserves heterochromatin organization and nuclear envelope integrity by sustaining HP1α-Lamin interactions, thereby suppressing transposable element (TE) activity. Pin1 loss induces early heterochromatin relaxation and LINE1 reactivation, activating the cGAS/STING/type I interferon pathway. Pin1 depletion further promotes TE-derived neoantigen generation and broadly remodels the tumor immune microenvironment, eliciting innate and adaptive immune responses that enhance tumor clearance. Genetic Pin1 depletion, or pharmacological inhibition with clinically available drugs, sensitizes fibrotic, immune-cold tumors to immune checkpoint blockade. These findings uncover a mechano-genomic mechanism of immune evasion in breast cancer and establish Pin1 as a therapeutic target to restore tumor immunogenicity and improve immunotherapy efficacy.

The efficacy of immune checkpoint blockade (ICB) in NSCLC depends on the tumor mutational burden (TMB). However, a fraction of patients with high TMB and predicted immunogenic neoantigens (neoAgs) do not respond. Here we show that in a model of highly mutated NSCLC, cross-presenting cDC1s are required to induce broad effector CD8+ T cell responses to both strong and weak endogenous neoAgs. Importantly, cDC1 amplification by Flt3L increases immunogenicity of MHC class-I neoepitopes and promotes tumor regression, whilst PD-L1 blockade is ineffective. cDC1 density correlates to CD8+ T cell scores and prognosis, particularly in hypermutated human NSCLC. Single-cell RNA sequencing reveals the molecular determinants of Flt3L-therapy including expansion of immunogenic lung cDC1 and proliferation of cytotoxic CD8+ T cells with reduced exhaustion. We conclude that boosting cDC1 activity is critical to leverage neoAgs content for therapeutic advantage in hypermutated lung tumors that do not respond to ICB.