Since the first cells on Earth about 4 billion years ago, the cell plasma membrane (PM) has served as the essential barrier to segregate the outside and create a safe internal environment for biochemical reactions. Meanwhile, the cell PM is also the first defender and sensor against external and internal perturbations. In theory, any perturbation that may severely disrupt the function of cell membranes should be recognized as a “challenge” and activate a multifactorial stress response, including innate immune responses.

However, at first sight, the loss of PM integrity may seem to be “lethal”, which irreversibly compromises the viability of cells. It may seem once an animal cell loses its PM integrity (e.g., due to membrane pore-forming), many critical cellular components, such as ions, proteins, and ATP, are all gone. Thus, due to lack of these key components, the dying/dead cells may be unable to make any reactions to “alert” the surroundings upon such PM damage, especially considering animal cells don’t have a rigid cell wall to support the cellular structures. Therefore, although PM damage is dangerous, it is not universally regarded as a dangerous signal (Danger-associated molecular pattern, DAMP) by the damaged cells.

The recent discovery of many PM repair machineries that can hold PM integrity after damage suggests that PM damage can be “sub-lethal” [1]. This means cells can tolerate certain membrane damage without lysis and sometimes come back to life and revive. During this “surviving” time, PM-damaged cells may recognize the sub-lethal PM integrity loss as an innate immune activation pattern, thus turning it into cellular responses, which may affect the immune microenvironment.

Recently, there have been comprehensive reviews of membrane repair mechanisms and their potential implications for health and disease [2], [3], [4], [5]. In this review, we will systematically summarize the evidence that cells can survive “sub-lethal” membrane damage, including from programmed cell death and non-specific PM perturbations; we will introduce the repair mechanisms of programmed cell death-elicited membrane damage, followed by the sections describing how non-specific PM disruption, such as from plaques and wound damage, can be repaired; last, we will propose a model to discuss how dying cells can sense sub-lethal PM integrity loss and change the landscape of the local immune-environments, in the pathological contexts.