Globally, the elderly population is experiencing significant growth, attributed to enhanced management of chronic diseases (1). In 2004, there were 461 million individuals aged 65 and older, and projections suggest this number will increase to 2 billion by 2050, posing unprecedented challenges for healthcare planning and delivery (2). Recognising ageing as a key factor in chronic conditions (3), the growing elderly population’s socio-economic impact has forced research to focus on the aspects of extending human health span (4).

Wound healing is a fundamental biological response, an intricate orchestration of events, offering a unique lens through which we can unravel the complexities of autoimmune disorders, ageing-related conditions, and the intricate landscape of cancer. The present review aims to underscore the important role of wound healing as a model for understanding these overarching biological processes. Autoimmunity, ageing, and cancer, seemingly different biological events, reveal interconnected threads that converge in the epicentre of wound healing. Central to this convergence is the orchestrating influence of inflammation, with interleukin-6 (IL-6) emerging as a key regulatory player. The structural parallels between tumours and wound healing have been recognised for decades, notably illustrated in the seminal work by Dvorak in 1986 (5). Recent insights emphasise the striking resemblance between granulation tissue, pannus-like tissue from chronic inflammation (such as progressive arthritis), and tissues attacked by viral infections, with the solid cancer stroma (6). These pathologies result in fibrotic tissue, also observed in conditions such as tissue fibrosis in the lungs of COVID-19 patients or the stroma of pancreatic ductal adenocarcinoma (PDAC) (6, 7).

We will delve into the stages of wound healing, exploring the dynamic interplay of cellular and molecular components. By unravelling the parallels between wound healing and autoimmune responses, investigating the impact of ageing on tissue regeneration, and scrutinising the intricate relationship between wound healing and cancer ecosystems, we aspire to elucidate the profound implications that a comprehensive understanding of wound healing holds for these complex biological phenomena. The spotlight on inflammation, especially IL-6, serves as the central key point, guiding our exploration where wound healing serves not only as a metaphor but also as a model for broader biological processes.

Wound healing is a dynamic process influenced by various factors, including the size and extent of the wound, microbial contamination, and the overall health and age of the individual. Failure to navigate this intricate process can result in chronic wounds or formation of hypertrophic/keloid scars (8–10). An intriguing aspect lies in the regenerative capacity of the interfollicular epidermis in humans, capable of full regeneration. In contrast, the repair of the dermal architecture in humans is a more intricate process leading to scar formation. This dermal repair unfolds through three/four distinct phases: blood clotting/haemostasis (potentially part of the inflammatory response), inflammation, proliferation, and maturation/remodelling. Epidermal regeneration occurs concurrently with dermal healing, and the restoration of the barrier integrity is completed during the process of re-epithelisation, while dermal remodelling continues for several weeks or months after (11). Despite the complexity and precision inherent in wound healing, this orchestrated process is not immune to interruptions and failures. Such disruptions can result in the development of non-healing/chronic wounds or pathological scars, underscoring the delicate balance required for successful tissue repair and regeneration (8). The vulnerability of the wound healing process to deviations emphasises the need for a nuanced understanding of its intricacies to develop effective interventions and therapies. The key events in the wound healing sequence have been described in detail previously (8, 12) and are summarised in Table 1 and Figure 1 .

Connective tissue, containing the intricate molecules of the ECM, is a universal component found in all organs. The deposition of ECM plays an irreplaceable role in the healing process. However, an imbalance between deposition and degradation can lead to organ fibrosis, resulting in scar formation, and significantly affecting the organ function (56). Inflammation further contributes to the formation of a pro-fibrotic microenvironment, with immune cells producing an array of cytokines, chemokines, and bioactive factors such as IL-4, IL-6, IL-13, TGF-β, and TNF-α. These factors activate fibroblasts and also shift their phenotype from α-smooth muscle actin-negative (α-SMA-, fibroblast-like) to α-smooth muscle actin-positive (α-SMA+, myofibroblast-like), which, in turn, contributes to ECM deposition and perpetuation of inflammation (57).

Organ fibrosis is a severe condition often leading to fatal outcomes, exemplified in complications of COVID-19 lung injury due to SARS-CoV-2 infection. The massive occurrence of myofibroblasts, coupled with cytokine dysregulation during the cytokine storm, particularly accompanied by elevated levels of IL-6, has systemic effects on the patients (6, 58, 59). Monitoring IL-6 levels in severe COVID-19 cases has been recommended for assessing the health status and adjusting therapeutic protocols to prevent exacerbation of complications (60). Therapeutic interventions targeting the IL-6 signalling pathway, such as anti-IL-6 receptor antibodies tocilizumab or sarilumab, have shown promise in managing these complications (61). In parallel, immune infiltration and the presence of myofibroblasts are common in autoimmune diseases such as the terminal stage of systemic sclerosis or Hashimoto’s thyroiditis (62, 63). The association of systemic sclerosis and other autoimmune diseases with cytokine dysregulation, including hyperproduction of IL-6, has been well-established (64, 65).

Desmoplastic stroma characterises the microenvironment of certain tumours, such as pancreatic ductal adenocarcinoma (PDAC), resembling scar-like fibrosis with numerous myofibroblasts playing a significant role (66, 67, 7). The controlling role of myofibroblasts, particularly in producing IL-6, underscores their potential significance in the stromal desmoplasia of tumours. This intricate interplay between immune response, fibrosis, and tumour microenvironment (TME) highlights the interconnectedness of these biological processes, offering novel avenues for therapeutic exploration.

Autoimmune diseases, characterised by the immune system targeting self-antigens, result in chronic inflammation-mediated tissue injury. Coined by immunologist Paul Ehrlich, the term “horror autotoxicus” captures the phenomenon of immune-mediated self-destruction (Ehrlich, 1900). Despite the immune system’s diverse mechanisms causing tissue damage in autoimmune diseases, fibrosis and impaired function frequently emerge as common features in these deleterious scenarios, demonstrating scleroderma and rheumatoid arthritis as extemporary examples (6).

Scleroderma, also known as systemic sclerosis, is a complex autoimmune disease characterised by fibrotic changes affecting both the skin and visceral organs (68). It leads to increased mortality, particularly due to cardiac disease, pulmonary fibrosis, and pulmonary hypertension. The disease progression is not effectively prevented by current immunosuppressive treatments, as they are only partially successful in halting fibrotic tissue accumulation. Histological examination reveals myofibroblasts as key drivers of fibrosis in scleroderma, and their resistance to apoptosis contributes to abundant collagen overproduction, elevated ECM stiffness, and heightened pro-fibrotic cytokine levels (69, 70). TGF-β (71) and IL-6 (72) are implicated in scleroderma pathogenesis, with IL-6 acting as a pro-fibrotic factor and correlating with disease severity. Inhibition of IL-6 has shown promise in preventing early lung disease progression in patients with systemic sclerosis. Combining different immunotherapies, such as CD47 and IL-6 blockade, has demonstrated efficacy in a murine model, hinting at potential benefits for patients (73).

Rheumatoid arthritis, another autoimmune inflammatory disease, is characterised by joint pain, swelling, and stiffness. Activated mesenchymal cells, particularly fibroblast-like synoviocytes, contribute to pathological tissue repair, leading to pannus formation and joint destruction (74). Extra-articular manifestations, including lung fibrosis, are common in rheumatoid arthritis, and elevated levels of IL-6 are frequently associated with the disease (75). While IL-6 participates in controlling articular and extra-articular pathologies, it is important to note that experiencing the cytokine storm, characterised by elevated IL-6 levels, is relatively rare in these patients (76). However, the autoimmune progression in rheumatoid arthritis can lead to cachexia and severe psychiatric issues, and anti-IL-6 therapy has shown efficacy in treating affected joints, alleviating extra-articular manifestations, stabilising lung fibrosis, and reducing cachexia (77). Notably, drugs such as tocilizumab and sarilumab have demonstrated good efficacy and tolerability in rheumatoid arthritis patients with a poor response to conventional treatments.

Inflammation is a natural process for tissue repair, but chronic inflammation, termed “inflammageing” in ageing individuals, can have adverse effects (78). Immunosenescence, age-related changes in the immune system, and increased cytokine secretion by adipose tissue contribute to chronic inflammation. Elevated levels of IL-6, IL-1, TNF-α, and C-reactive protein in older individuals are linked to higher morbidity and mortality (79), with TNF-α and IL-6 serving as frailty markers. In this context, chronic wounds often stall at the inflammatory stage, where pro-inflammatory cytokines such as TNF-α, IL-1 (α and β), and IL-6 play important roles in signalling immune cell recruitment, angiogenesis, and epithelisation (80). These cytokines, primarily secreted by immune cells but also by epithelial cells, fibroblasts, and endothelial cells, are major components of the senescent secretome. IL-1α, in particular, can stimulate the expression of other cytokines in senescent cells, reinforcing the pro-inflammatory senescence-associated secretory phenotype. The chronic presence of senescent cells in the WME may enhance inflammation and hinder its resolution, contributing to impaired wound healing if the inflammatory stage persists. Understanding this interplay is essential for developing effective interventions in chronic wound management.

In addition to the inflammageing issue, proper wound healing involves transient senescence marked by up-regulated cell cycle arrest proteins (p16, p21, p53) and SASP (81, 82). Studies in mice demonstrate impaired wound healing upon selective elimination of senescent cells, while senescent fibroblasts and endothelial cells, expressing PDGF-AA as part of the senescence-associated secretory phenotype, actively promote wound healing (81). In ageing, the altered senescence response contributes to delayed wound healing, with studies showing improved outcomes in aged mice by inhibiting p21 expression (83). Chronic wounds, such as venous and diabetic ulcers, exhibit senescent fibroblasts, and their presence correlates with decreased healing rates (84). Persistent senescent cells can lead to chronic wounds, emphasising the importance of transient senescence. Additionally, senescent fibroblasts, induced by oxidative stress, regulate the fibrotic response by inhibiting proliferation and matrix synthesis (85), with CCN1 triggering senescence and anti-fibrotic gene expression (86). This complex interplay of senescence dynamics plays a crucial role in regulating the trajectory of wound healing, scarring, and fibrosis.

Organogenesis, an intricate ballet of prenatal events encompassing cell proliferation, differentiation, migration, ECM deposition, intercellular interactions, and programmed cell death, orchestrates the correct formation and function of organs. Any deviations during this developmental course can significantly affect the architecture and subsequent function of an organ. In a conceptual shift, malignant solid tumours can be likened to organs, orchestrated by genetically aberrant cancer cells. Their interaction with non-cancer cells, including connective tissue cells, inflammatory cells, and blood vessels, plays a significant role in shaping their aberrant function and subsequent dissemination (87). The connective tissue component, often referred to as the stroma, is a dynamic entity within malignant tumours. It houses fibroblasts producing ECM, growth factors, chemokines, cytokines, matrix metalloproteinases (MMPs), as well as vessels supplying nutrition and oxygen to the tumour (88).

The stroma, far from being a passive bystander, actively participates in the tumour’s dynamic processes. The ECM influences cancer cell adhesion and migration, with proteolytic enzymes remodelling it to create channels facilitating cancer cell migration (11, 89). Furthermore, the stroma acts as a platform for immune cell infiltration into the tumour site. Despite cancer cells expressing numerous neo-antigens due to frequent mutations, the anticancer activity of immune cells is often down-regulated by products of various cell types in the cancer ecosystem. For instance, tumour-associated macrophages may paradoxically support cancer cell growth and spread (90). Accordingly, the intricate dialogue between immune cells and cancer cells opens new horizons in anticancer therapy. Therapeutic manipulation of this dialogue, exemplified by immune checkpoint inhibitors, proves to be a powerful anticancer strategy that enhances the quality of life and life expectancy for many oncological patients (91). Understanding the complexity of the tumour as an organ and deciphering the interplay between its cellular components paves the way for innovative approaches in cancer treatment and management.

Cancer is a genetic disease, grounded in fundamental gene alterations that drive its onset. The molecular scrutiny of individual cancer cells constituting the bulk has unequivocally revealed the heterogeneous nature of tumours, with metastatic cells often displaying significant distinctions from their counterparts in primary tumours (92, 93). Cancer cells, rather than existing in isolation, intricately collaborate with non-cancer cells, which play indispensable roles in fostering cancer cell growth and systemic dissemination. These non-cancer cells actively contribute to shaping a cancer-supporting microenvironment, typically characterised by pro-inflammatory conditions.

Central to the orchestration of tissues and organs are adult tissue stem cells, reliant on specific microenvironments to sustain their stemness. Extending this hypothesis to cancer stem cells suggests that non-cancer cells within the cancer ecosystem and their products actively participate in establishing the niche supportive of cancer stem cell maintenance (94, 95). As cancer progresses, the tumour evolves under the selective pressures exerted by endogenous mechanisms, including the microenvironment, immunity, and exogenous factors such as anticancer therapies (96).

Tumour-associated macrophages (TAM), cancer-associated fibroblasts (CAFs), and various types of lymphocytes are significant components within the cancer ecosystem, each contributing distinctive elements to the intricate milieu (97). Given the scope of this review, our focus will delve into the roles of TAMs and CAFs.

The onset of paraneoplastic syndromes may serve as an early warning sign, indicating an underlying health issue. These syndromes typically arise from chronic inflammation, with IL-6 playing a pivotal role and contributing to the dysregulation of blood plasma proteins (155). Many paraneoplastic syndromes exhibit significant biological activity, leading to systemic effects (130). Examples of syndromes not directly linked to cancer therapy are detailed in Table 2 . Skin, muscles, joints, the nervous system, and endocrine glands appear particularly responsive to inflammation-associated dysregulation associated with cancer development (155). In addition to hormones produced by cancer cells, factors supporting inflammation seem implicated in many paraneoplastic syndromes. These syndromes are not strictly tumour type-specific and are observed in both leukaemias and solid tumours. Furthermore, cancer treatments, including immune checkpoint inhibitors (156), may exacerbate paraneoplastic syndromes, highlighting the potential role of cell disintegration in therapy-related manifestations (157). While the application of anti-IL-6 receptor antibody tocilizumab has a minimal impact on cancer growth, it can reduce the occurrence of paraneoplastic syndromes (158, 159).

Cancer and ageing share several systemic similarities. Ageing is a complex process influenced by various endogenous and exogenous factors, with chronic inflammation being a hallmark (169, 170). In aged individuals, including humans, there is an elevated level of inflammation-supporting factors in the serum compared to younger counterparts (171–173). High levels of IL-6, both in absolute numbers and when expressed as a ratio to albumin, can predict mortality in seriously ill elderly individuals (174, 175) and may impact cognitive functions in the aged population (176). Similar to cancer cachexia, age-related sarcopoenia in the elderly is associated with increased inflammation-supporting factors (177). The mechanisms of age-related cachexia are not fully understood, but it is hypothesised that chronic inflammation in ageing is linked to the dysregulation of iron metabolism (178). Another explanation for elevated pro-inflammatory activity in the elderly may be differences in intestinal microbiota and intestinal permeability (179). Collectively, these age-dependent differences are referred to as inflammageing, as mentioned above, and can contribute to various age-related disorders (180). Given the negative impact of elevated cytokine levels on the physiological functions of the elderly, reducing inflammation could be a promising avenue to enhance the quality of life for seniors. Some approaches, such as incorporating dietary soy isoflavonoids and proteins, show promise (181). Monitoring inflammation-supporting factors in the serum of polymorbid older individuals is relevant in clinical medicine. The high levels of these cytokines associated with age-related frailty could serve as indicators to identify cancer patients who may not benefit from therapy and could even face a risk of reduced life quality (182).

It has been shown that the formation of wound-healing granulation tissue featuring α-SMA-rich myofibroblasts is a linking point of various pathological conditions such as wound healing, autoimmune inflammation, tissue fibrosis, post-serious infection status, cancer, and age-associated frailty. Central to these processes is the cytokine IL-6 and its signalling pathway (183, 184). IL-6, a glycoprotein of 184 amino acids (MW 23.7kDa), is produced by immune cells and, notably, by non-immune cells such as myofibroblasts. Its function hinges on receptor expression. The transmembrane IL-6 receptor interacts with the signal transducer (gp130) upon IL-6 binding, initiating signalling. However, the IL-6 receptor can also be found in biological fluids. When unoccupied, the IL-6 receptor undergoes enzymatic cleavage from its transmembrane domain, releasing it into the extracellular space. Once interacting with IL-6 and signal transducers, this soluble IL-6 receptor can then dock to the membrane and initiate signalling (185). The immune function, primarily initiation of the immune response, and other functions – spanning from wound healing to cancer – rely on the type of cells that express membrane receptors. This involves docking of the complex of soluble receptors with IL-6 to permissive cells. The non-immune functions encompass epithelial cell proliferation and migration, along with the production of ECM by fibroblasts and neovascularisation.

Given the IL-6’s impact on cancer-related processes, therapeutic modulation of its signalling axis holds promise. A range of drugs, from antibodies to small inhibitors targeting IL-6 signalling, have been developed. These interventions include blocking IL-6 synthesis and its receptor, neutralising IL-6, inhibiting its binding to the IL-6 receptor, and disrupting the interaction of the IL-6 receptor with gp130 (186). Anti-IL-6 therapy, exemplified by the widely used anti-IL-6 receptor humanised monoclonal antibody tocilizumab, is a common practice in rheumatology (187). Moreover, tocilizumab was successfully employed in treating COVID-19-induced cytokine storms in indicated patients (188). A similarly positive effect was also observed with the use of the anti-IL-6 antibody siltuximab, although it was not as commonly utilised as tocilizumab (189). Unfortunately, clinical studies attempting to influence IL-6 interaction with the receptor complex in anticancer treatment were not entirely successful (184). It is suggested that inhibition of Jak/Stat3, which is involved in the signalling pathways of various cytokines, chemokines, and growth factors, including IL-6, could be more effective (190, 186). A combination of anti-IL-6 signalling therapy with other anticancer drugs or drugs inhibiting chronic inflammation in the TME may be more appropriate (190, 191). Another potential approach could involve the use of drugs with dual effects, such as targeting both the IL-6 receptor and mitochondria, representing a promising model for complex therapy (192).

Of note, the potential systemic effects of IL-6 produced by the TME, including CAFs, on cancer wasting, cachexia, and paraneoplastic syndromes are detailed in the chapters “Functions of CAFs” and “Paraneoplastic syndromes”.

Inflammation influences wound healing, solid cancer progression and spreading, with cytokines, notably IL-6, playing a central role. During wound healing, macrophages and fibroblasts in the granulation tissue are the main contributors to IL-6 production, enhancing wound re-epithelisation. Closure of the wound prompts termination of new granulation tissue deposition, starting the maturation/remodelling phase. Complications such as bacterial infections or foreign body contamination may prolong healing, introducing inflammation and overproduction of myofibroblasts leading to hypertrophic scarring or keloid formation. This scenario mirrors inflammation seen in autoimmune disorders or viral infections (e.g., COVID-19), often resulting in fibrosis, which can be severe and fatal.

Solid tumours follow a similar narrative, as the cancer stroma, featuring CAFs, resembles the granulation tissue of healing, complete with myofibroblasts, akin to the proliferation phase of wound healing. However, in cancer, the granulation tissue-like stroma does not undergo shutdown, and the dialogue between cancer cells and stromal elements persists endlessly, facilitated by the unlimited proliferation of cancer cells ( Figures 3A, B ). Chronic wounds, autoimmune conditions, and cancer converge in their systemic impact on the patient, leading to frailty, wasting, and cachexia, ultimately compromising the quality of life and contributing to mortality.

The present review weaves narratives under the theme of inflammation, orchestrated by the paracrine secretion of cytokines and chemokines, with IL-6 taking a central role – a ubiquitous cytokine with intricate effects. Wound healing, considered a primary event, is repurposed in autoimmunity and cancer, offering valuable insights into understanding cancer regulation and informing potential anticancer therapies. Although therapies targeting the IL-6 axis have not met all expectations, combining them with other anticancer approaches or employing drugs with multiple targets in cancer ecosystems may prove beneficial in the hopefully near future.