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Deregulated WNT signaling has been shown to favor malignant transformation, tumor progression, and resistance to conventional cancer therapy in a variety of preclinical and clinical settings. Accumulating evidence suggests that aberrant WNT signaling may also subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to multiple immunotherapeutics, including immune checkpoint blockers. Here, we discuss the molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance and present potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy. Highlights Canonical WNT signaling plays a central role in embryogenesis, tissue homeostasis, and wound repair. Deregulated WNT signaling is involved in virtually all stages of oncogenesis. Impaired anticancer immunity as a result of aberrant WNT signaling is emerging as a key contributor to tumor progression and resistance to treatment. Activation of canonical WNT signaling hampers T cell-mediated anticancer immune responses by multiple mechanisms including immune exclusion. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are widely used for the management of disease- or therapy-related complications in cancer patients. Recent data indicate that activation of GC receptors (GRs) precipitates breast cancer progression by favoring metastatic dissemination and cell survival at distant sites. These findings call for the re-evaluation of GC usage in patients with cancer. [ABSTRACT FROM AUTHOR]

Large BAX/BAK pores that form during apoptosis enable mitochondrial nucleoids to access the cytosol, potentially leading to inflammatory signaling via CGAS. Under physiological conditions, however, BAX/BAK-dependent caspase activation rapidly dismantles dying cells to prevent inflammatory responses. BAX and BAK operate at the interface between apoptotic signaling and innate immunity control. [ABSTRACT FROM AUTHOR]

Demaria and colleagues have recently identified three prime repair exonuclease 1 (TREX1) as a key determinant for the limited immunogenicity of cancer cells responding to single high-dose radiation. TREX1 stands out as a promising target for the development of novel strategies to boost anticancer immune responses driven by radiation therapy (RT). [ABSTRACT FROM AUTHOR]

Autophagy not only constitutes a robust barrier against malignant transformation at the cell-intrinsic level, but also contributes to the organismal control of potentially oncogenic cells. Recent data provide molecular insights into the mechanisms whereby oncogene hyperactivation induces autophagy to establish a permanent proliferative arrest commonly known as cellular senescence. [ABSTRACT FROM AUTHOR]

Recent findings demonstrate that transient genetic inhibition of autophagy promotes age-associated pathologies in mice. While autophagy restoration effectively counteracts such disorders, it also exacerbates the incidence of various solid and hematological tumors. These data may cast additional shadows on the clinical potential of autophagy inhibition for cancer therapy. [ABSTRACT FROM AUTHOR]

Tumor progression and resistance to treatment are often accompanied by the polarization of malignant cells towards a mesenchymal or poorly differentiated state. Such a transition generates an accrued vulnerability to the induction of ferroptosis, potentially paving the way to novel therapeutic strategies for targeting residual disease in patients with cancer. [ABSTRACT FROM AUTHOR]

At odds with its nuclear counterpart, extranuclear promyelocytic leukemia constitutively inhibits autophagy, hence limiting cancer progression. These data raise the interesting possibility that some tumor suppressors have become specialized to operate at multiple subcellular compartments for counteracting different aspects of the oncogenic process. [ABSTRACT FROM AUTHOR]

Recent findings (Tsabar et al.) demonstrate that human cancer cells that evade the cell cycle blockage normally imposed by DNA damage experience sustained p53 signaling upon MDM2 degradation by caspase 2. Such a response may be connected to the delivery of immunostimulatory signals to ensure the elimination of genetically instable cancer cells. [ABSTRACT FROM AUTHOR]

Bcl-2 proteins are widely known as key controllers of mitochondrial outer membrane permeabilization, arguably the most important step of intrinsic apoptosis. Accumulating evidence indicate that most, if not all, members of the Bcl-2 protein family also mediate a number of apoptosis-unrelated functions. Intriguingly, many of these functions ultimately impinge on cell fate decisions via apoptosis-dependent or -independent mechanisms, delineating a complex network through which Bcl-2 family members regulate cell survival and death. Here, we critically discuss the mechanisms through which Bcl-2 proteins influence cell fate as they regulate autophagy, cellular senescence, inflammation, bioenergetic metabolism, Ca2+ fluxes, and redox homeostasis. The Bcl-2 protein family is widely known for controlling mitochondrial outer membrane permeabilization (MOMP), a key step in apoptotic cell death. Most, if not all, Bcl-2 family members have been shown to influence cellular processes apparently unrelated to apoptosis. Regulation of autophagy, cellular senescence, inflammation, bioenergetic metabolism, Ca2+ fluxes, and redox homeostasis by Bcl-2 proteins ultimately impacts on cell fate. Modulating the Bcl-2 protein family holds promise as a potential therapeutic approach for numerous diseases beyond cancer. [ABSTRACT FROM AUTHOR]

Evolving neoplasms accumulate non-synonymous mutations at a high rate, potentially enabling the expression of antigenic epitopes that can be recognized by the immune system. Since they are not covered by central tolerance, such tumor neoantigens (TNAs) should be under robust immune control as they surge. However, genetic defects that impair cancer cell eradication by the immune system coupled with the establishment of local immunosuppression can enable TNA accumulation, which is generally associated with improved clinical sensitivity to various immunotherapies. Here, we explore how tumor-intrinsic factors and immunological processes shape the mutational and antigenic landscape of evolving neoplasms to influence clinical responses to immunotherapy, and propose strategies to achieve robust immunological control of the disease despite disabled immunosurveillance. Highlights The recognition of TNAs by the host immune system has a key role in natural immunosurveillance and dictates the outcome of most (if not all) current cancer (immuno)therapies. A panel of tumor-intrinsic and microenvironmental factors influence TNA evolution over space and time, partially explaining the heterogeneity of clinical responses to (immuno)therapies. The tumor and its host coevolve in a highly dynamic manner, which shapes the mechanisms whereby progressing neoplasms evade immune recognition as they become resistant to (immuno)therapy. Unveiling the trajectories of TNA evolution may help define quantitative, qualitative, and temporal aspects of the anticancer immune response that can assist clinical decision-making. [ABSTRACT FROM AUTHOR]

Several insults cause the inner mitochondrial membrane to abruptly lose osmotic homeostasis, hence initiating a regulated variant of cell death known as ‘mitochondrial permeability transition’ (MPT)-driven necrosis. MPT provides an etiological contribution to several human disorders characterized by the acute loss of post-mitotic cells, including cardiac and cerebral ischemia. Nevertheless, the precise molecular determinants of MPT remain elusive, which considerably hampers the development of clinically implementable cardio- or neuroprotective strategies targeting this process. We summarize recent findings shedding new light on the supramolecular entity that mediates MPT, the so-called ‘permeability transition pore complex’ (PTPC). Moreover, we discuss hitherto unresolved controversies on MPT and analyze the major obstacles that still preclude the complete understanding and therapeutic targeting of this process. [ABSTRACT FROM AUTHOR]