Cancer immunotherapies have significantly improved patient survival, yet achieving durable remission remains a major challenge due to tumors’ immune evasion mechanisms. This limitation reveals critical gaps in our understanding of immune surveillance and immunoediting, concepts primarily derived from infectious disease models that view immune responses as destructive. The widely accepted self-nonself (SNS) model reinforces this perspective, framing immune cells as destroyers of foreign pathogens while tolerating self-tissues. However, this view may miss essential immune functions beyond cytotoxicity. The integrity model suggests that immune cells preserve tissue integrity by suppressing autoreactive T cells. In contrast, the adaptation model posits that autoreactive immune cells play a key role in tissue homeostasis, even in malignancy. Disruptions in cellular stability can activate immune responses to restore tissue integrity and reshape the tumor microenvironment to inhibit tumor growth. Conventional immunotherapies, which focus on amplifying cytotoxic activity, may inadvertently worsen tissue disruption, fostering conditions that promote cancer progression despite temporary tumor shrinkage. By shifting from tumor eradication to immune-driven tissue homeostasis, this model offers a transformative approach. Here, we argue that future breakthroughs may lie in harnessing immune mechanisms that enhance tissue adaptability, providing a curative immunotherapy for cancer. This work was supported by funding from the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. This work was also supported by P30 CA 016059. Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Background/Objectives: Preclinical and clinical evidence supports a chaperone-based vaccination platform for cancer immunotherapy. The objective of this study is to interrogate the next generation of chaperone-based immune modulator, termed Flagrp170, which was constructed by fusing a defined NF-κB-activating microbial sequence with a large stress protein with a superior antigen-holding/presenting property in the setting of antigen-targeted cancer vaccination. Methods: Bone marrow-derived dendritic cells were treated with Flagrp170 protein or an unmodified parental chaperone molecule (i.e., Grp170), followed by an analysis of DC activation and DC-mediated T cell priming using both in vitro and in vivo models. Antitumor vaccine responses in mice receiving tumor antigens (e.g., gp100, Her2/neu) complexed with Flagrp170 or Grp170 were examined through multiple immune assays. The potential use of a Flagrp170-based chaperone vaccine to sensitize tumors to anti-PD-1 therapy was also evaluated. Results: Flagrp170 not only retains the intrinsic ability of the parent chaperone to facilitate antigen cross-presentation, but also acquires a unique capacity to stimulate DCs efficiently through the engagement of TLR5-NF-κB signaling. This chimeric chaperone shows superior activity compared to the unmodified parental molecule, resulting in enhanced DC activation and T cell priming. Vaccination with Flagrp170 complexed to tumor antigens induces a robust T cell response against primary tumors and metastases, a process critically dependent on CD8+ DCs. Additionally, the Flagrp170 chaperone vaccine can efficiently generate and expand tumor-reactive T cells. The consequent remodeling of the tumor microenvironment towards a Th1/Tc1 dominant immune phenotype significantly potentiates cancer responsiveness to anti-PD1 therapy. Conclusions: Given the safety and T cell stimulation profiles of the chaperone–antigen complex vaccine already established in our recent clinical trial, this new generation of chaperone cargo, capable of delivering both antigenic targets and pathogen-associated immunoactivating signals simultaneously, represents a promising strategy to potentially improve the low response rates in patients receiving immune checkpoint inhibitors.

Immunology progresses not merely by accumulating data but by evolving the conceptual lenses through which those data are interpreted; yet for six decades the self-non-self/infectious-non-self (SNS/INS) paradigm-casting allogeneity as activating signal and 'self' as intrinsically tolerogenic-has dominated research design, peer review and curriculum. This, in turn, systematically amplifies concordant findings while attenuating evidence for tissue integrity, metabolic, symbiotic and network-centric cues. This conceptual monoculture appears as a hidden dogma that impedes breakthroughs in our understanding of the immune system and the development of curative therapies. By institutionalising theoretical immunology as a formal discipline and treating models as explicit, testable tools rather than hidden assumptions, immunologists can sharpen hypothesis generation and achieve a better understanding of existing data. This essay provides an overview of empirically grounded theoretical models to counter monoculture, clarify how frames shape interpretation, and expand the field's conceptual toolkit.

The exact functionality of hepatic immune cells in nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain poorly understood. Utilizing a systems immunology approach, we identified that the reciprocal cell-cell communication networks operate through a dominant-subdominant pattern of ligand-receptor signaling pathways, primarily involved in homeostasis. In healthy controls, immune responses mainly function through homeostatic pathways. Chronic consumption of a Western diet (WD) altered hepatocyte function and led to communication events dominated by hepatic stellate cells (HSCs), cancer cells, and NKT cells, with 80% of NKT cells involved in hepatic homeostasis during NAFLD. During NAFLD-induced HCC, 80% of all immune cells, specifically NKT cells and monocytes, collaborated with hepatocytes and myofibroblasts to restore liver homeostasis. Dietary correction strategies during NAFLD led to divergent outcomes: HCC development was associated with failure to maintain homeostatic immune responses, while tumor prevention correlated with sustained homeostatic immune responses driven mainly by monocytes. Importantly, only 5% of T and NKT cells exhibited apoptosis-inducing functions, mainly engaged in homeostatic turnover of fibroblasts and myofibroblasts. Our results suggest that effective anti-tumor immune responses operate as a system via tissue homeostatic pathways that modulate the microenvironment, rather than direct cytotoxicity against tumors. This work was supported by funding from NIH R01DK105961, 2017-MIP-2, the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under W81XWH2210793, the National Center for Advancing Translational Sciences under UL1TR002649, and the VCU Cancer Mouse Models Core Shared Resource supported, in part, by Cancer Center Support Grant P30 CA 016059. Computational and Systems Immunology (COMP)

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.

Chemotherapy-induced tumor dormancy is a major barrier to curative cancer therapy, particularly in triple-negative breast cancer (TNBC), where dormant residual cells evade treatment and fuel late relapses. To define survival mechanisms sustaining dormancy, we examined four breast cancer models: HER2-positive murine MMC and human SK-BR-3, and TNBC murine 4T1 and human MDA-MB-231. Dormancy was induced with low-dose FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Across all models, dormant cells maintained high Bcl-xL expression. shRNA knockdown of Bcl-xL increased chemotherapy-induced apoptosis and prevented relapse in vitro and in vivo. Pharmacologic inhibition with A-1331852 improved chemotherapy, particularly in TNBC, and transient dosing avoided compensatory Survivin induction. Systemic A-1331852 suppressed relapse but caused off-target toxicity, whereas intratumoral delivery preserved efficacy and safety but failed to eliminate early lung dissemination, as confirmed by ex vivo culture of dormant tumor cells. Notably, disseminated cell frequency inversely correlated with primary tumor size during neoadjuvant chemotherapy, underscoring the need for systemic therapies targeting distant dormant cells. These findings identify Bcl-xL as a central survival factor in chemotherapy-induced dormancy, and suggest that tumor-targeted systemic delivery of A-1331852 may eradicate disseminated dormant cells and prevent metastatic relapse in high-risk TNBC.

Traditional organ transplantation relies on the Self-Non-self (SNS) model of immunity, focusing on donor-recipient compatibility and aggressive immunosuppression to prevent acute rejection. Although effective early, this strategy does not prevent chronic rejection and cannot account for operational tolerance, failure of perfectly HLA-matched grafts, or the occasional spontaneous acceptance of a fully mismatched organ. The adaptation model of immunity offers a different lens. In the thymus, "central adaptation" programs T cells to recognise self-peptide-MHC (pMHC) so they can later recognise different tissues to facilitate tissue repair and homeostasis. Whether a graft thrives or fails depends on how quickly this self-oriented circuitry can operate. Autografts and isografts arrive with their own extracellular-matrix (ECM) "memory", and recipient T cells immediately recognise their pMHC, triggering tissue-remodelling responses. Allografts must adapt to new ECM-a transition that is associated higher levels of graft injury allowing indirect antigen presentation. Until adaptation is complete, recipient T cells mount cytotoxic rather than reparative responses because of antigen cross-presentation, during which the graft relies on donor-derived tissue-resident memory T cells (TRM) to maintain integrity. Therapeutically, interventions that preserve or expand graft-borne TRM, or that pharmacologically enhance adaptation-receptor signalling, could hasten this donor-to-host reprogramming. By replacing blanket immunosuppression with targeted promotion of tissue-remodelling immunity, the adaptation model charts a path toward long-term graft survival without the lifelong risks of today's regimens.

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear.MethodsIn a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumour inhibition upon dietary correction.ResultsCarcinogenesis begins during MAFLD, with tumour cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to the turnover of liver cells but do not primarily target the tumour. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response-not merely immune activation-dictates whether tumours grow or regress, emphasising the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming.ConclusionThese findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumour-hostile microenvironment, whereas tumour-directed approaches fail to remodel the TME. This underscores the need for tissue remodelling strategies in cancer prevention and treatment.

The quest for a curative cancer immunotherapy remains elusive, hindered by a longstanding focus on tumor cell elimination through cytotoxic mechanisms. However, mounting evidence points to an underappreciated dimension of immune function: its capacity for tissue remodeling and homeostasis, which can shape a tumor-inhibitory microenvironment. This perspective review highlights the adaptation model of immunity, which reframes the immune response as a dual force capable of both preserving and disrupting tissue integrity. Central to this model is Signal IV, a novel pathway in which self-reactive immune cells interact with adaptation receptors (AdRs) on tissue cells through adaptation ligands (AdLs) on immune cells. This interaction activates anti-apoptotic pathways in target cells, enabling immune responses to promote tissue survival and homeostasis even in the presence of cytotoxic mediators. Crucially, the downregulation of AdRs in stromal cells, while preserved in malignant cells, creates a tumor-promoting microenvironment, whereas the reverse fosters tumor rejection. This paradigm challenges conventional approaches by shifting the focus from tumor cell destruction to restoring tissue integrity, offering a revolutionary framework for immunotherapy. By targeting the AdR–AdL axis to reprogram the tumor microenvironment, the adaptation model proposes a transformative strategy for harnessing immune responses to achieve durable cancer control.

Our understanding of the immune response is far from complete, missing out on more detailed explanations that could be provided by molecular insights. To bridge this gap, we introduce the quantum model of T-cell activation. This model suggests that the transfer of energy during protein phosphorylation within T cells is not a continuous flow but occurs in discrete bursts, or 'quanta', of phosphates. This quantized energy transfer is mediated by oscillating cycles of receptor phosphorylation and dephosphorylation, initiated by dynamic 'catch-slip' pulses in the peptide-major histocompatibility complex-T-cell receptor (pMHC-TcR) interactions. T-cell activation is predicated upon achieving a critical threshold of catch-slip pulses at the pMHC-TcR interface. Costimulation is relegated to a secondary role, becoming crucial only when the frequency of pMHC-TcR catch-slip pulses does not meet the necessary threshold for this quanta-based energy transfer. Therefore, our model posits that it is the quantum nature of energy transfer-not the traditional signal I or signal II-that plays the decisive role in T-cell activation. This paradigm shift highlights the importance of understanding T-cell activation through a quantum lens, offering a potentially transformative perspective on immune response regulation.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Abstract Breast cancer (BCa) mortality is mainly due to distant recurrence of the disease associated with the establishment of tumor dormancy following initially successful treatment of early-stage breast cancer. Current clinical practice for cancer survivors is a “wait and watch” approach without any therapeutic or relapse preventing interventions, except for ER-positive BCa patients who receive hormone therapy, yet remain at risk of tumor recurrences. In attempt to identify a molecular target in dormant tumor cells, we discovered upregulation of Bcl-xL in chemotherapy-induced dormant tumor cells. To target such survival pathway in FVBN202 transgenic mouse model of neu-overexpressing breast cancer, we first established tumor dormancy by means of a low dose immunogenic chemotherapy (FAC, 5-FU + Adriamycin + Cyclophosphamide) of the neu-overexpressing mouse mammary carcinoma (MMC) while using a specific inhibitor of Bcl-xL, A-1331852. Such combination therapy in vitro resulted in the inhibition of chemotherapy-induced tumor relapse. In addition, selective knockdown of Bcl-xL in MMC by means of shRNA prevented relapse of chemotherapy-induced dormant tumor cells. Our findings suggest tumor-targeted delivery of A-1331852 during chemotherapeutic treatment of early-stage breast cancer for the prevention of distant recurrences of the disease.

Supplementary Figure 2 from Immune-Induced Epithelial to Mesenchymal Transition In vivo Generates Breast Cancer Stem Cells

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of focusing on detailed specific cell types and missing the collective function of the hepatic immune system. To discover the collective immune function, we take systems immunology approach by performing high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Such pattern discovery approach recognized direct role of the innate immune cells in the progression of NASH and HCC. These data suggest that discovery of the immune pattern not only detects the immunological mechanism of HCC in spite of dynamic changes in immune cells during the course of disease but also offers immune modulatory interventions for the treatment of NAFLD and HCC.

Current treatments are ineffective to cure or prevent occurrences of autoimmune psoriasis and psoriatic cardiovascular disease/CVD. Psoriasis is associated with deregulated expressions of human endogenous retroviruses (ERVs) variants. ERV transcripts and proteins are detected in lesioned biopsies—without assembled viral particles—in addition to antibody and T-cell responses against ERV-K dUTPase. In persons living with HIV-1, manifestations of psoriasis are exacerbated variably. These may depend on multiple factors, differences in ERVs expressions, subtypes of HIV-1, and/or epigenetics. This article represents a quantitative risk assessment and meta-analysis approach with an attempt to assess causality. We surmise that mutated ERVs trigger aberrant proliferation and differentiation of keratinocytes, which in turn induce proinflammatory polarization. Independent risk factors and/or covariates with a range of relative risk/RR ratios appear to significantly impact the development of autoimmune psoriasis or immune intolerance, plausibly through ERVs genes activity. Given the antihypertensive drug’s potential in psoriasis development, a probable role in promising either ERVs activation or perturbations in epigenetic factors is questionable. Although the correlational nature of the data based on RR ratios prevents making robust conclusions, we reckon that the likelihood of attributable risk factors for certain antihypertensive drugs may stem from their pleiotropic effects or potentials for inducing ERV-mediated dysregulation of keratinocytes and/or endothelial cells. These findings expand our knowledge regarding ERV activations and HIV-1, antihypertensive drugs use, and incidents of psoriatic disease, and call for exploring cell-specific therapies aimed at blocking or reversing mutated ERVs gene activity toward attaining stable remissions in psoriasis and associated CVD.

Supplementary Figure Legends 1-5, Methods from Immune-Induced Epithelial to Mesenchymal Transition In vivo Generates Breast Cancer Stem Cells

Supplementary Figure S2. Schematic depiction of construction of human MDA-7/IL-24-encoding lentivirus (LV-MDA-7) and engineering of T cells.

Tumor cells are genetically unstable carrying continuously changing mutations which are the basis for neoantigen vaccines. Pre-existing immune responses against tumor-associated self-antigens as well as against semi-nonself neoantigens have been reported in cancer patients. These data are against the self-nonself (SNS) model of immunity, proposing that tumor cells expressing self-antigens induce tolerance. The adaptation model proposes that expression of many adaptation receptors (AdRs) linked to anti-apoptotic pathways in tumor cells, one of which is reported to be B7-H1, is responsible for the survival of tumor cells in the presence of anti-tumor immune responses. To this end, anti-tumor efficacy of immune checkpoint inhibitors is mainly because of the blockade of survival pathway in tumor cells downstream of B7-H1. Limited efficacy of these therapies is because several AdRs may be expressed by tumor cells which compensate for the blockade of B7-H1. In fact, B7-H1 is mischaracterized as PD-L1 ligand while it is a bi-directional receptor that relays survival signal both as trans, when engaged with PD-1 on T cells, and as cis, when both B7-H1 and PD-1 or B7.1 are expressed on DCs or tumor cells. AdRs could also exist as a dual receptor system consisting of those linked to anti-apoptotic pathways, i.e., TNFR2, and countered by those linked to pro-apoptotic pathways, i.e. TNFR1. The outcomes of tumor-reactive T cell responses would depend on the presence/absence of AdRs or balance between an AdR and its counter-receptor on tumor cells. Therefore, current immunotherapies should focus on the discovery and inhibition of tumor-associated AdRs, or knocking out the nominal AdLs in tumor-specific T cells. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under Award No. W81XWH2210793. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense. This work was also supported by multi-investigator pilot funding from the VCU Massey Cancer Centre, supported in part with funding from NIH/NCI Cancer Centre support grants P30 CA016059.